Our latest publications

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Dufour, Damien; Strøm, Yunna Erika & Bjørås, Magnar [Show all 11 contributors for this article] (2026). Transient SUMOylation inhibition in human pre-adipocytes stably imprints a transcriptional beiging fate. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(6), p. 1–22. doi: 10.1093/nar/gkag232. Full text in Research Archive Show summary

  SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how perturbation of the SUMOylation pathway impacts adipocyte plasticity remains unclear. Here, we show that brief pharmacologic inhibition of SUMOylation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure produces changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and RNA-sequencing revealed immediate chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements at thermogenic enhancers, and increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling and stabilization of beiging transcription activators. We propose that transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity.

• Lindstad, Tuva Marie; Pourteymour, Shirin; Lee-Ødegård, Sindre; Drevon, Christian André & Norheim, Frode Amador (2026). Structured Exercise Interventions and Hepatic-Metabolic Outcomes in Adults with MASLD: A Narrative Review of Randomized Controlled Trials. International Journal of Molecular Sciences. ISSN 1661-6596. 27(7). doi: 10.3390/ijms27072941. Full text in Research Archive
• Yadav, Ajay; Richartz, Nina; Bhagwat, Sampada; Burman, Marta Maria; Munthe-Kaas, Monica Cheng & Skålhegg, Bjørn Steen [Show all 9 contributors for this article] (2026). Starvation of leukemic cells enhances DNA damage-induced apoptosis in vitro via ROS/p38 MAPK and prevents leukemia progression in fasting xenograft mice. Journal of Biological Chemistry. ISSN 0021-9258. 302(3). doi: 10.1016/j.jbc.2026.111143. Full text in Research Archive Show summary

  Most children with acute lymphoblastic leukemia (ALL) achieve long-term survival due to intensive multimodal chemotherapy. However, the use of cytotoxic DNA-damaging agents is frequently associated with severe long-term side effects, prompting continued efforts to improve treatment strategies. This study explores the potential of starving the leukemic cells to enhance the efficacy of DNA-damaging therapy in ALL. Previous work demonstrated that cAMP signaling attenuates DNA damage-induced apoptosis in ALL cells, both in vitro and in a xenograft model. The current findings show that glucose and serum deprivation reverse the effect of cAMP, converting it from a survival factor to a promoter of DNA damage-induced apoptosis in ALL-derived cell lines and patient-derived leukemic cells in vitro. The starvation-induced sensitization was independent of p53 but was shown to require increased levels of reactive oxygen species (ROS). In turn, the elevated ROS levels enhanced the activation of the mitogen-activated protein kinase p38 (p38 MAPK). The resulting augmented cell death was inhibited both by the ROS scavenger N-acetyl cysteine and the p38 MAPK inhibitor SB 202190. The translational potential of increasing the efficacy of DNA damaging agents in starving ALL cells was supported by in vivo data showing that intermittent fasting, combined with subtherapeutic doses of irradiation, significantly inhibits the leukemia progression in a xenograft model of severe combined immunodeficiency mice.

• Aunan, Anine; Claeyssen, Charlotte; Abdelhalim, Mohamed & Ruzzin, Jerome Nicolas Marius (2026). Transcriptomic profiling of co-cultured cancer-host cells identifies hypoxia as a driver of the skeletal muscle cell’s anti-proliferative effect on cancer cells | Oncogenesis. Oncogenesis. doi: 10.1038/s41389-026-00601-9. Full text in Research Archive Show summary

  Cancer metastasis is the leading cause of cancer-related death. While organs such as the lung are hotspots for metastases, others -like skeletal muscle- remain rarely colonized, a phenomenon that remains poorly understood. In this study, we show that EO771 breast cancer cells proliferated robustly when co-cultured with MLg lung stromal cells, whereas their proliferation was restrained when maintained in direct contact with differentiated C2C12 skeletal muscle myotubes. Notably, these effects were not cell-type-specific, as similar results were obtained with 4T1 breast cancer cells and Sol8 myotubes. After two days of co-culture, both cancer and host cells (MLg and C2C12) exhibited distinct niche-specific transcriptional remodeling. Strikingly, the poorly proliferative EO771 cells co-cultured with C2C12 myotubes acquired a hypoxia-associated gene-expression signature despite normoxic conditions (~20% O₂), showing that muscle cells reprogram cancer cells into a hypoxic, anti-proliferative state. Under hypoxic conditions, we confirmed that the depletion of oxygen allows C2C12 cells to nearly abolish EO771 proliferation. Neither exogenous lactate, culture acidosis, their combination, altered glucose levels, nor conditioned medium could reproduce the suppressive environment created by C2C12 myotubes. In contrast, MLg cells induced minimal transcriptional changes in EO771 cells and were themselves broadly reprogrammed by the cancer cells. Moreover, hypoxia enhanced EO771 proliferation in MLg co-cultures, emphasizing the permissive nature of the MLg environment. Collectively, these findings uncover a unique, paradoxical, muscle-induced pseudo-hypoxic program that restricts cancer cell proliferation. They also highlight the need for caution in targeting hypoxia signaling in anti-metastatic therapies, as such interventions could weaken skeletal muscle’s natural defense against tumor colonization.

• Bartkeviciene, Arenida; Jasukaitiene, Aldona; Zievyte, Inga; Ivanauskiene, Sandra; Stachneviciute, Gabija & Jenceviciute, Kornelija [Show all 16 contributors for this article] (2025). Baseline AHR expression shapes immune response to pharmacological modulation in PBMCs from pancreatic cancer patients. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1655258. Full text in Research Archive Show summary

  Background: Pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive to immunotherapy because of its highly immunosuppressive tumor microenvironment. Aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, has emerged as a key regulator of immune homeostasis and inflammation. However, its systemic immunomodulatory role in PDAC, particularly outside the tumor microenvironment, remains poorly understood. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with PDAC and healthy donors were isolated and treated ex vivo with two AHR agonists (Carbidopa and Tapinarof) and one antagonist (BAY 2416964). The samples were stratified into Low and High/Medium AHR expression groups. Flow cytometry (FC), qPCR, ELISA, Luminex assays, and immunofluorescence imaging were used to evaluate immune checkpoint expression, cytokine secretion, monocyte polarization, and subcellular AHR localization. Overall survival analysis was performed based on the baseline AHR expression levels. Results: Baseline AHR expression strongly influenced the immunological effects of AHR modulators. In High/Medium AHR PBMCs, Carbidopa increased PD-L1 and soluble PD-1 (sPD-1) levels, while IL10 expression was suppressed. In contrast, BAY significantly reduced PD-1 and sPD-1 levels in Low AHR PBMCs, whereas Tapinarof induced the highest IL10 expression. All modulators reduced the proportion of M2-like monocytes, indicating a shift toward less immunosuppressive phenotypes. Nuclear translocation of AHR protein varied across treatments and expression levels. Kaplan–Meier analysis revealed a non-significant trend toward improved overall survival in the High/Medium AHR group (log-rank p = 0.276). Conclusion: Baseline AHR expression critically shapes the immune response to pharmacological modulation in PBMCs from PDAC patients. These findings suggest that AHR profiling may serve as a clinically relevant biomarker for stratifying patients and guiding personalized immunotherapy approaches for PDAC.

• Park, Johan & Skålhegg, Bjørn Steen (2025). Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer – a brief update. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1680838. Full text in Research Archive Show summary

  The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, offering durable responses in multiple malignancies by targeting regulatory pathways such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These pathways, which normally maintain immune tolerance and homeostasis, can be exploited by tumors to evade immune surveillance. Dual blockade using monoclonal antibodies (mAbs) targeting PD-1/PD-L1 and CTLA-4 has shown synergistic effects, improving response rates, overall survival, and progression-free survival in several cancer types. The U.S. Food and Drug Administration (FDA) has approved two such combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab, based on demonstrated clinical benefit in melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, pleural mesothelioma, and esophageal squamous cell carcinoma. However, clinical benefit has not been consistent across all tumor types, with limited efficacy observed in cancers such as glioblastoma, head and neck squamous cell carcinoma, and Merkel cell carcinoma. Additionally, combination therapy is associated with a higher incidence of immune-related adverse events, affecting multiple organ systems and necessitating careful dosing strategies to balance efficacy and toxicity. This review summarizes the current landscape of FDA-approved PD-1/PD-L1 and CTLA-4 combinations, their therapeutic achievements, clinical limitations, and supports future research in combination immunotherapy.

• Grimolizzi, Franco (2025). How regenerative is “regenerative”? A quantitative score to benchmark therapy performance across tissues. Regenerative Medicine. ISSN 1746-0751. 20(12), p. 707–713. doi: 10.1080/17460751.2026.2626080. Full text in Research Archive
• Wik, Jonas Aakre; Berge, Emma Riiser; Strømsnes, Kristine Bakklund & Skålhegg, Bjørn Steen (2025). Metabolism in the tumor microenvironment: implications for pathogenesis and therapeutics. Frontiers in Immunology. 16, p. 1–20. doi: 10.3389/fimmu.2025.1610255. Full text in Research Archive Show summary

  The immune system protects the body against dangers that include pathogens, damage and cancer. Modern cancer therapies have sought to bolster immune responses against cancer using immunotherapy, which may include various forms of immune checkpoint therapy (ICT) in addition to methods of adoptive cell transfer (ACT), which is often associated with transfer of chimeric antigen receptor (CAR) T cells. Despite favorable outcomes in some patients and some cancers, as many as 60-80% of patients fail to benefit from ICT due to primary or adaptive resistance. This highlights the need for deeper understanding of how cancers suppress the immune system. Solid tumors, which make up approximately 90% of all cancers, are characterized by an immunosuppressive tumor microenvironment (TME). A hallmark of the TME is dysfunctional vascularization and impaired perfusion, which hinder effective drug delivery and promote hypoxia-induced metabolic reprograming in both cancer and immune cells. As the TME imposes intense metabolic stress through nutrient competition and lactate-driven acidification – both of which activates immunosuppressive pathways, targeting the TME itself may be beneficial in enhancing the efficacy of immunotherapy. Here we will briefly discuss the potential of targeting the metabolism of the TME as a means to promote normalized tumor vascularization and/or enhance anti-tumor immune responses.

• Doncheva, Atanaska; Higa, Ryoko; Khanal, Prabhat; Ingebrigtsen, Martine Villemo Øksenvåg; Li, Yuchuan & Kolan, Shrikant [Show all 16 contributors for this article] (2025). Elevated adipose inflammation, but reduced hepatic triacylglycerol storage in diet-induced obese Plin4/mice. Journal of Biological Chemistry. ISSN 0021-9258. 302(2). doi: 10.1016/j.jbc.2025.111043. Full text in Research Archive
• Dufour, Damien; Bryne, Sandra Kristine Stølen; Dapsance, Florian; Ferrito, Noemi; Plotton, Ingrid & Dalen, Knut Tomas [Show all 9 contributors for this article] (2025). Mechanisms of sexually dimorphic adipose tissue remodelling upon prolonged breastfeeding. bioRxiv (preprint article). doi: 10.1101/2025.09.05.674416. Full text in Research Archive Show summary

  Early developmental cues exert lasting influence on the adipose tissue function and the metabolic health throughout adulthood. In mice, adipose tissue remodelling during the weaning transition programs long-term tissue plasticity, setting its capacity for expansion and thermogenesis in response to environmental stimuli. However, the mechanisms driving this remodelling, and the role of weaning-associated dietary changes in this process, are unknown. Here, we characterise the emergence of sexually dimorphic patterns of adipose tissue distribution and function during the post-weaning period. As subcutaneous adipocytes acquire a white phenotype, the tissue microenvironment undergoes a coordinated remodelling, including reduced innervation and an increase in immune cell content. Using a model of prolonged breastfeeding, we show that it promotes adipose tissue expansion through sex-dependent mechanisms, stimulating progenitor proliferation in males and adipocyte hypertrophy in females. In males, this is accompanied by accelerated tissue whitening, which we link to enhanced clearance of extracellular noradrenaline by mature adipocytes. Our findings reveal sex- and diet-dependent mechanisms governing adipose tissue maturation and highlight how early life nutritional cues shape the microenvironment and function of mature adipocytes. Highlights - The peri-weaning period associates with sexually dimorphic remodelling of the adipose tissue - Whitening of the adipose tissue associates with immune infiltration and decrease innervation in both sexes - Prolonged breastfeeding prevents drop in proliferation in males - Whitening is accelerated in males during prolonged breastfeeding

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Strøm, Yunna Erika; Bjørås, Magnar & Enserink, Jorrit [Show all 10 contributors for this article] (2025). Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate. bioRxiv (preprint article). 54(6). doi: 10.1101/2025.03.07.642034. Full text in Research Archive Show summary

  Abstract SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.

• Zhou, Zhenqi; Moore, Timothy M.; Strumwasser, Alexander R.; Ribas, Vicent; Iwasaki, Hirotaka & Morrow, Noelle [Show all 36 contributors for this article] (2025). Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males. Cell Reports Medicine. 6(5). doi: 10.1016/j.xcrm.2025.102116. Full text in Research Archive Show summary

  Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

• Stukas, Darius; Zievyte, Inga; Ivanauskiene, Sandra; Karvelyte, Gabriele; Jasukaitiene, Aldona & Bartkeviciene, Arenida [Show all 12 contributors for this article] (2025). Small-molecule inhibitor BAY synergizes with gemcitabine through AHR inhibition in pancreatic cancer cells. Biochemical Pharmacology. ISSN 0006-2952. 233. doi: 10.1016/j.bcp.2025.116798. Full text in Research Archive Show summary

  Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatment effectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT–PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30–41%, whereas activation decreased the response by 11–28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.

• Hjorth, Marit; Egan, Casey L; Telles, Guilherme D; Pal, Martin; Gallego-Ortega, David & Fuller, Oliver K [Show all 31 contributors for this article] (2025). Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice. Journal of Sport and Health Science. ISSN 2095-2546. 14. doi: 10.1016/j.jshs.2024.100991. Full text in Research Archive Show summary

  Purpose Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. The purpose of this study was to examine the mechanisms behind the protective effects of exercise. Methods We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden. Results We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved. Conclusion Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

• Jeltema, Devon; Knox, Kennady; Dobbs, Nicole; Tang, Zhen; Xing, Cong & Araskiewicz, Antonina [Show all 11 contributors for this article] (2025). PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 222(5). doi: 10.1084/jem.20241184. Full text in Research Archive Show summary

  Type I IFN (IFN-I) induce hundreds of antiviral genes as well as negative regulators that limit IFN-I signaling. Here, we investigate the family of 16 PARPs and find that 11 PARPs are ISGs, of which 8 PARPs inhibit IFN-I production. PARP7 is the most potent negative feedback regulator of IFN-I production. Using Parp7−/− and Parp7H532A/H532A mice, we show that PARP7 loss leads to systemic autoimmunity characterized by splenomegaly and increased autoantibodies and inflammatory cytokines. PARP7 loss also results in perivascular immune infiltration in the lung that forms tertiary lymphoid structures. Mechanistically, PARP7 inhibits multiple innate immune pathways in a cell-intrinsic and MARylation-dependent manner. PARP7 interacts with IRF3 through the catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production. Irf3−/− or Irf3S1/S1 (transcription defective) or Sting−/− rescues Parp7H532A/H532A mouse autoimmunity and lung disease. Together, our study reveals physiological functions of PARP7 as a negative feedback regulator of IFN-I production that maintains immune homeostasis particularly in the lung.

• Kannen, Vinicius; Olafsen, Ninni Elise; Das, Siddhartha; Giuliana, Paolo; Izzati, Fauzia N. & Choksi, Hani [Show all 16 contributors for this article] (2025). Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration. Biochemical Pharmacology. ISSN 0006-2952. 236, p. 1–12. doi: 10.1016/j.bcp.2025.116872. Full text in Research Archive
• Hindar, Kjetil; Bodin, Johanna Eva; Dalen, Knut Tomas; Duale, Nur; Garseth, Åse Helen & Malmstrøm, Martin [Show all 14 contributors for this article] (2025). Overview of methods for production of sterile salmonids, their applicability in aquaculture and possible implications to wild salmon populations and biodiversity in Norway. VKM Report. 2025(02), p. 1–92. doi: https:/vkm.no/risikovurderinger/allevurderinger/steriloppdrettsfiskeffekterpabiologiskmangfold.4.6b6641cb18a179b6780ab2db.html. Full text in Research Archive Show summary

  VKM has assessed the positive and negative effects on biodiversity were sterile salmon to be used in Norwegian aquaculture. Triploidisation is assessed as the most effective method for sterilising fish, but it can affect the welfare and health of the fish. Several other techniques for producing sterile salmon are being tested, but it is too early to determine whether they can be used in large-scale farming. This is the key message in a knowledge summary VKM has prepared for the Norwegian Environment Agency. Background Escaped farmed salmon poses a major threat to wild salmon in Norway. hey can interbreed with wild salmon, genetically alter them, and make the populations less adaptable and more vulnerable to disease and environmental changes. A possible solution to the problem may be to use sterile salmon in farming. To date, only triploidisation has been tested. Newly fertilised eggs are given a hydrostatic pressure shock, thereby retaining an extra set of chromosomes which render the fish sterile. This method is currently the only one tested on a large scale. Triploidisation is effective but can also pose health and welfare challenges to fish. Methods VKM has reviewed available scientific literature regarding methods that can be used to produce sterile salmon. VKM has assessed whether these methods work as well, or better, than triploidy and whether they are likely to have fewer negative effects on fish welfare. Assessments have also been made of whether farmed fish treated with other sterilisation methods pose a greater or lesser threat to wild salmon than traditional farmed salmon. VKM has looked at the possibilities for further development of the triploidisation technique and has also assessed various methods currently being tested for producing sterile fish. Some of these are still at the laboratory-testing stage, while others are approaching trials with release into sea-pens. VKM has grouped the different methods based on whether they cause permanent changes in the genome (so-called "knock-out" of important genes) or whether the changes only result in temporary blocking or downregulation of gene expression (so-called "knock-down"). Results VKM concludes that triploidisation remains the most effective method and that there are possibilities to further develop this methodology through targeted breeding and adjustments in how the fish are kept. These measures can potentially solve the challenges for fish health and welfare. Using pure triploid female lines can also reduce some of the other challenges by preventing spawning interactions in rivers and reducing disease transmission to wild salmon. Alternative sterilisation methods, such as gene editing, vaccination, and temporary downregulation of proteins for gonad development using antisense oligomers and egg immersion, are promising but still under development. VKM assesses that methods causing permanent changes in the genome of diploid fish have a higher inherent risk than methods that only affect gene expression. Hope in egg-bathing Perhaps the most promising technique for safe production of sterile salmon is to add synthetic oligonucleotides to the eggs at an early stage, thereby preventing germ cell development without causing any inheritable changes. Such oligonucleotides can be injected into the eggs or absorbed by the eggs through bathing (immersion) in a special solution. "Especially the method involving targeted 'tools,' such as oligonucleotides that prevent germ cell development and can be added to the eggs in a water bath, seems promising," says Johanna Bodin, member of the Panel for Genetically Modified organisms and spokesperson for the report. (...)

• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Hamfjord, Julian; Nebdal, Daniel Johan Hammer; Lehtiö, J. & Lingjærde, Ole Christian [Show all 8 contributors for this article] (2025). Elevated KRAS protein level is associated with better survival in pancreatic cancer. BMC Cancer. 25. doi: 10.1186/s12885-025-14461-w. Full text in Research Archive Show summary

  Background Activating somatic KRAS mutations in hotspot loci occur almost universally (> 95%) in pancreatic ductal adenocarcinoma (PDAC). Both the presence of a KRAS mutation and high mRNA expression levels of KRAS in tumor tissue have been associated with worse outcome. Less is known about the expression of KRAS at the protein level and its association with clinical and molecular parameters. In the present study, we investigated the prognostic significance of the KRAS protein level and its relation to KRAS mutation status and the mRNA expression level. Methods A total of 41 PDAC tumors were screened for seven KRAS mutations (p.G12D, p.G12V, p.G12R, p.G12C, p.G12S, p.G13D, p.G12A) by the Wobble-enhanced ARMS method. Whole transcriptome and proteome profiles were obtained using mRNA microarrays (Agilent) and quantitative mass spectrometry-based proteomics (HiRIEF LC–MS/MS), respectively. The clinical outcome was overall survival (OS). Results KRAS mutations were identified in 88% of the tumors with p.G12D and p.G12V mutations being the most frequent. Tumors with p.G12V mutation had significantly higher KRAS mRNA expression than tumors with p.G12D, p.G12C, p.G12R or no mutation identified (P < 0.01). KRAS protein levels did not associate significantly to neither KRAS mRNA levels (Spearman’s rho = 0.18, P = 0.28) nor type of KRAS mutation. High KRAS protein level and mutation p.G12V were found to be significantly associated with better (P < 0.01) and worse OS (P < 0.05), respectively. Conclusions The KRAS protein level correlated poorly with KRAS mRNA expression level and was not significantly associated with the type of mutation present. Interestingly, we found that patients with high KRAS protein level in their tumors had a better clinical outcome.

• Kolnes, Kristoffer Jensen; Nilsen, Emelie; Brufladt, Steffen Johnsen; Meadows, Allison; Jeppesen, Per Bendix & Skattebo, Øyvind [Show all 17 contributors for this article] (2025). Effects of seven days’ fasting on physical performance and metabolic adaptation during exercise in humans. Nature Communications. 16(1). doi: 10.1038/s41467-024-55418-0. Full text in Research Archive Show summary

  Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5’ AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2025). Body mass index and risk of connective and soft tissue cancer: results from a large cohort of 1.7 million individuals in Norway. BMC Cancer. 25. doi: 10.1186/s12885-025-13637-8. Full text in Research Archive Show summary

  Background Few studies have investigated the association between adiposity and connective and soft tissue cancer, a rare and understudied cancer entity. We investigated this association in a large cohort of more than 1.7 million individuals in Norway. Methods The study cohort included 1,723,692 men and women aged 16–75 years at baseline in 1963–1975. Data on weight and height measurements from the Norwegian Tuberculosis Screening Programme were linked to the Cancer Registry. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between body mass index (BMI) and risk of connective and soft tissue cancer, adjusting for age and sex. Results In total 1758 connective and soft tissue cancer cases were registered during 56.1 million person-years of follow-up. The HRs (95% CIs) for the BMI categories of 15-<18.5, 18.5-<25.0 (reference), 25.0-<30.0, 30.0-<35.0, ≥ 35.0 were 0.77 (0.50–1.20), 1.00 (reference), 1.15 (1.03–1.27), 1.28 (1.06–1.54), and 1.69 (1.21–2.37, ptrend<0.0001). The HR per 5 kg/m2 increment in BMI was 1.14 (1.07–1.22) overall, 1.10 (0.99–1.23) in men and 1.17 (1.08–1.27) in women. Obesity in early adulthood (age 16–29 years) showed a suggestive positive association with connective and soft tissue cancer risk with HR (95%CIs) of 1.73 (0.95–3.16), ptrend=0.09) when compared to normal weight. No clear association was observed between BMI and early-onset (age < 50 years at diagnosis) connective and soft tissue cancer. Positive associations were observed between BMI and soft tissue sarcoma, fibrosarcoma, dermatofibroma, and lipoleiomyoma, but no clear associations were observed with fibrous histiocytoma and liposarcoma. Conclusion These results suggest that higher BMI overall and in early adulthood may be associated with increased risk of connective and soft tissue cancer, but BMI seems not to influence early-onset disease. Large cohort studies with more detailed information on confounding factors and BMI trajectories over time are needed for further verification before firm conclusions can be made.

• Pandey, Deepak; Doncheva, Atanaska Ivanova; Sapkota, Rumakanta; Jüterbock, Alexander Oliver; Viswanath, Kiron & Dalen, Knut Tomas [Show all 7 contributors for this article] (2025). Dietary inclusions of the brown macroalgae, Ascophyllum nodosum and Fucus vesiculosus, favourably modulate fat deposition and the caecal microbiome of obese mice. Food Bioscience. ISSN 2212-4292. 68. doi: 10.1016/j.fbio.2025.106590. Full text in Research Archive Show summary

  Effective preventive measures are needed to lower the global incidence of obesity in humans. We investigated whether the dietary inclusions of brown macroalgae Ascophyllum nodosum (AN) or Fucus vesiculosus (FV) prevent diet-associated obesity development in mice by modulating the gut microbiome and body composition. Female C57BL/6J mice were fed a low-fat control, high-fat (HF), or HF diet with 5 % inclusion of whole AN or FV biomass for 12 weeks. Body composition, whole-body energy metabolism, caecal microbiome, and liver transcriptomics were evaluated. Mice fed AN and FV-added HF diets had lower gonadal (∼30 %), subcutaneous (∼25 %), and total (∼40 %) fat mass compared to the mice fed the HF diet, although the differences were statistically non-significant. Macroalgae-supplemented diet groups had reduced Firmicutes: Bacteroidota ratios and lower abundances of obesity-associated bacterial genera, including Lachnoclostridium, Lachnospiraceae, Lactococcus, Romboutsia, and Tuzzerella in the caecal contents, compared to the HF diet group (more prominently with FV-supplementation). These bacteria were found to be positively associated with fat mass gain. On the other hand, macroalgal addition promoted certain leanness-associated and short-chain fatty acids-producing bacteria, where FV-addition most prominently enriched Alistipes, Akkermansia, Muribaculum, and Oscillospiraceae NK4A214 group, while AN-addition highly promoted the Bacteroides. This study shows that dietary inclusion of AN or FV in the HF diet promotes a unique and healthier gut microbiota and lowers the HF diet-associated fat mass gain in mice.

• Rundblad, Amanda; Das, Siddhartha; Ginos, Bigina N.R; Matthews, Jason; Holven, Kirsten Bjørklund & Voortman, Trudy [Show all 7 contributors for this article] (2025). Exposure to fine particulate matter in adults is associated with immune cell gene expression related to inflammation, the electron transport chain, and cell cycle regulation. Environmental Epigenetics. 11(1). doi: 10.1093/eep/dvaf008. Full text in Research Archive Show summary

  Exposure to air pollution and an unhealthy built environment increase disease risk by impacting metabolic risk factors and inflammation, potentially via epigenetic modifications and effects on gene expression. We aimed to explore associations between fine particulate matter (PM2.5), black carbon, ozone, nitrogen dioxide, distance to nearest water body, normalized difference vegetation index, and impervious surface and gene expression profiles in adults. This study is a part of the LongITools project and includes cross-sectional data from the Rotterdam Study, a population-based cohort study, and NoMa, a randomized controlled trial. Environmental exposures were assigned using land-use regression (LUR) models and satellite data. Gene expression was assessed with whole blood RNA sequencing (Rotterdam Study, n = 758) and microarray analyses in peripheral blood mononuclear cells (NoMa, n = 100). We analysed transcriptomic profiles and enriched pathways associated with each of the environmental exposures. PM2.5 had the strongest gene expression associations, while only a few significant associations were observed for the other environmental exposures. In both populations, exposure to PM2.5 was associated with genes and pathways related to inflammation, oxidative stress, DNA metabolism, cell cycle regulation, histones, electron transport chain, oxidative phosphorylation, and neural signalling. This study is limited by different methods for RNA quantification, a cross-sectional design, and a small sample size. However, in both populations, exposure to PM2.5 resulted in the maximum number of associations with gene expression. In conclusion, PM2.5 is strongly associated with various gene expression profiles, which provide information about the underlying mechanisms of the detrimental health effects of exposure to PM2.5.

• Li, Gaoyang; Kolan, Shrikant; Grimolizzi, Franco; Sexton, Joseph; Malachin, Giulia & Goll, Guro Løvik [Show all 12 contributors for this article] (2025). Development of machine learning models for predicting non-remission in early RA highlights the robust predictive importance of the RAID score-evidence from the ARCTIC study. Frontiers of Medicine. ISSN 2095-0217. 12. doi: 10.3389/fmed.2025.1526708. Full text in Research Archive Show summary

  Introduction: Achieving remission is a critical therapeutic goal in the management of rheumatoid arthritis (RA). Despite methotrexate being the cornerstone of early RA treatment, a significant proportion of patients fail to achieve remission. This study aims to predict 6-month non-remission in 222 disease-modifying antirheumatic drug (DMARD)-naïve RA patients initiating methotrexate monotherapy, using baseline patient characteristics from the ARCTIC trial. Methods: Machine learning models were developed utilizing twenty-one baseline demographic, clinical and laboratory features to predict non-remission according to ACR/EULAR Boolean, SDAI and CDAI criteria. The model employed a super learner algorithm that combine three base algorithms of elastic net, random forest and support vector machine. The model performance was evaluated through five independent unseen tests with nested 5-fold cross-validation. The predictive power of each feature was assessed using a composite measure derived from individual algorithm estimates. Results: The model demonstrated a mean AUC-ROC of 0.75-0.76, with mean sensitivity of 0.77-0.81, precision (also referred to as Positive Predictive Value) of 0.77-0.79 and specificity of 0.63-0.66 across the criteria. Predictive power analysis of each feature identified the baseline Rheumatoid Arthritis Impact of Disease (RAID) score as the strongest predictor of non-remission. A simplified model using RAID score alone demonstrated comparable performance to the full-feature model. Conclusion: These findings highlight the potential utility of baseline RAID scorebased model as an effective tool for early identification of patients at risk of nonremission in clinical practise.

• Aune, Dagfinn; Mala, Tom; Myklebust, Tor Åge; Nordsletten, Marie Wiborg; Robsahm, Trude Eid & Saeed, Usman [Show all 8 contributors for this article] (2024). The association between body mass index and vulvar and vaginal cancer incidence: findings from a large Norwegian cohort study | Cancer Causes & Control. Cancer Causes and Control. ISSN 0957-5243. 36(2), p. 191–198. doi: 10.1007/s10552-024-01930-z. Full text in Research Archive Show summary

  There is limited evidence of potential associations between body mass index (BMI) and risk of vulvar and vaginal cancer. We explored these associations in a large cohort of Norwegian women. The analytical dataset included 889,441 women aged 16–75&nbsp;years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and vulvar and vaginal cancer incidence. During 30.1 million person-years of follow-up, 1748 incident vulvar and 408 incident vaginal cancer cases occurred. The HRs (95% CIs) for vulvar cancer for a BMI of 15- &lt; 18.5, 18.5- &lt; 25, 25- &lt; 30, 30- &lt; 35, ≥ 35 were 0.62 (0.38–1.01), 1.00 (reference), 1.23 (1.10–1.40), 1.43 (1.23–1.66) and 1.72 (1.35–2.20, ptrend &lt; 0.001), and per 5&nbsp;kg/m2 increment was 1.20 (1.13–1.26). The corresponding HRs (95% CIs) for vaginal cancer were 1.05 (0.52–2.15), 1.00, 0.89 (0.71–1.12), 0.95 (0.68–1.34), and 2.01 (1.29–3.13, ptrend &lt; 0.001), respectively, and per 5&nbsp;kg/m2 was 1.11 (0.99–1.25). The HR (95% CI) per 5&nbsp;kg/m2 increase in BMI at ages 16–29 was 1.28 (1.07–1.54, n = 250 cases) for vulvar and 1.53 (1.11–2.11, n = 66 cases) for vaginal cancers. The HR (95% CI) per 5&nbsp;kg/m2 for early-onset (&lt; 50&nbsp;years age at diagnosis) vulvar cancer was 0.92 (0.66–1.28, n = 87 cases) and 1.70 (1.05–2.76, n = 21 cases) for vaginal cancer. These results further support the associations between higher BMI and increased risk of vulvar and vaginal cancers, with suggestive stronger associations between BMI in early adulthood for both cancers and for early-onset vaginal cancer. Further studies are needed to elucidate these findings and investigate the underlying mechanisms.

• Medin, Anine Christine; Andersen, Lene Frost; Fadnes, Lars Thore; Lillegaard, Inger Therese Laugsand; Madsen, Lise & Mangschou, Bente [Show all 12 contributors for this article] (2024). Beregning og vurdering av i hvilken grad høringsutkast til nye kostråd vil dekke behov og anbefalinger for næringsstoffer. VKM Report. 2024(6), p. 1–79. Full text in Research Archive Show summary

  Vitenskapskomiteen for mat og miljø (VKM) har vurdert om Helsedirektoratets høringsutkast til nye kostråd fra 22. mars dekker næringsstoffanbefalingene for voksne, inkludert gravide og ammende.' Oppdraget er gitt av Helsedirektoratet, som en del av arbeidet med å revidere kostrådene, og VKMs beregninger og vurderinger er basert på høringsutkastet. VKMs rapport med resultatene fra oppdraget publiseres samtidig som kostrådene. VKMs rapport og konklusjonerne som presenteres gjelder høringsutkast til kostråd, slik de forelå 22. mars 2024. Basert på VKMs arbeid, har Helsedirektoratet valgt å justere enkelte av kostrådene, slik at kritiske næringsstoffer vil dekkes bedre i de endelige kostrådene som ble publiseres 15. august, parallelt med publisering av VKMs rapport. Hovedkonklusjon fra VKMs rapport: VKM konkluderer at et kosthold i tråd med høringsutkastet til nye kostråd sannsynligvis kan være tilstrekkelig for å dekke næringsstoffanbefalingene for de fleste vitaminer og mineraler for de fleste voksne, med noen unntak. Vurderingen omfatter to scenarioer – lavt og høyt – basert på utkast til kostrådene. Disse to scenarioene representerer henholdsvis de laveste og høyeste mengdene av matvaregruppene som omfattes av utkastet til kostrådene; lavt kostrådsscenario og høyt kostrådsscenario. VKM har kun beregnet næringsinnholdet for maten fra mengdene i utkast til kostråd, ikke for det totale kostholdet. –Vi har vurdert om næringsinnholdet dekkes hvis man følger de foreslåtte kostrådene, slik de forelå i mars. Vi konkluderer med at å følge disse sannsynligvis kan være tilstrekkelig for å dekke næringsstoffanbefalingene for de fleste vitaminer og mineraler for de fleste voksne, hvis man spiser et kosthold basert på de høyeste mengdene av matvaregruppene i kostrådsutkastet, sier faglig leder Anine Medin, som har ledet VKMs arbeid. VKMs resultater viser at innholdet av de fleste beregnede vitaminer og mineraler synes å være tilstrekkelig for kvinner og menn i alle aldere ved et kosthold i tråd med høyt kostrådsscenario. Innholdet av vitamin D, kalsium (kun unge voksne), jern (kun kvinner i fertil alder), sink (kun menn) og selen vil imidlertid sannsynligvis kunne være for lavt for en mindre andel kvinner og menn ved et kosthold som tilsvarer høyt scenario. Beregningene viser at i et kosthold i tråd med lavt kostrådsscenario, ligger innholdet av flere næringsstoffer lavere enn i høyt scenario. Innholdet av riboflavin, kalsium, jern (kun kvinner i fertil alder), sink, jod og selen vil sannsynligvis kunne være for lavt for en betydelig andel kvinner og menn ved et kosthold som tilsvarer lavt scenario. Videre vil innholdet av vitamin D, vitamin B6, folat, kalium, og jern (kun menn) kunne være for lavt for en mindre andel kvinner og menn. Gravide og ammende står i en særstilling, fordi de har høyere behov for næringsstoffer enn den øvrige befolkningen. Slik er beregningene og vurderingene gjort VKM har laget to kostrådsscenarioer basert på mengder av ulike matvaregrupper, som er gitt i høringsutkastet eller som tilleggsinformasjon fra Helsedirektoratet underveis i arbeidet med rapporten. Eksempelvis inneholder det lave scenarioet 500 gram frukt og grønnsaker, mens det høye scenarioet inneholder 800 gram. Det lave scenarioet inneholder ikke egg, ost eller rødt kjøtt, mens høyt scenario inneholder ett egg om dagen, to osteskiver om dagen og 350 gram rødt kjøtt i uken. Begge scenarioene inneholder eksempelvis også 90 gram fullkorn per dag. Valget av matvarer fra matvaregruppene som er inkludert i scenarioene er basert på ordlyden i kostrådene, samt innsikt fra nasjonale kostholdsundersøkelser. For å vurdere sannsynligheten til om disse scenariene inneholder tilstrekkelig med næringsstoffer, har VKM vurdert dem opp mot næringsstoffanbefalingene.

• Kannen, Vinicius; Grant, Denis M. & Matthews, Jason (2024). The mast cell-T lymphocyte axis impacts cancer: Friend or foe? Cancer Letters. ISSN 0304-3835. 588. doi: 10.1016/j.canlet.2024.216805. Full text in Research Archive
• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Bastani, Nasser Ezzatkhah; Nebdal, Daniel J.H.; Lingjærde, Ole Christian & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2024). Preoperative profiles of plasma amino acids and derivatives distinguish periampullary cancer and benign disease. BMC Cancer. 24(1). doi: 10.1186/s12885-024-12320-8. Full text in Research Archive Show summary

  Periampullary cancers, including pancreatic ductal adenocarcinoma, ampullary-, cholangio-, and duodenal carcinoma, are frequently diagnosed in an advanced stage and are associated with poor overall survival. They are difficult to differentiate from each other and challenging to distinguish from benign periampullary disease preoperatively. To improve the preoperative diagnostics of periampullary neoplasms, clinical or biological markers are warranted. In this study, 28 blood plasma amino acids and derivatives from preoperative patients with benign (N = 45) and malignant (N = 72) periampullary disease were analyzed by LC-MS/MS. Principal component analysis and consensus clustering both separated the patients with cancer and the patients with benign disease. Glutamic acid had significantly higher plasma expression and 15 other metabolites significantly lower plasma expression in patients with malignant disease compared with patients having benign disease. Phenylalanine was the only metabolite associated with improved overall survival (HR = 0.50, CI 0.30–0.83, P < 0.01). Taken together, plasma metabolite profiles from patients with malignant and benign periampullary disease were significantly different and have the potential to distinguish malignant from benign disease preoperatively.

• Pourteymour, Shirin; Fan, Jingxue; Majhi, Rakesh Kumar; Guo, Shuyuan; Sun, Xin & Huang, Zhen [Show all 21 contributors for this article] (2024). PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 81(331). doi: 10.1007/s00018-024-05372-3. Full text in Research Archive Show summary

  The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE−/− mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.

• Lee-Ødegård, Sindre; Hjorth, Marit; Olsen, Thomas; Moen, Gunn-Helen Øiseth; Daubny, Emily & Evans, David M [Show all 17 contributors for this article] (2024). Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis. eLIFE. 13, p. 1–25. doi: 10.7554/ELIFE.96535. Full text in Research Archive Show summary

  Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.

• Viken, Jonas Krag; Olsen, Thomas; Drevon, Christian André; Hjorth, Marit; Birkeland, Kåre Inge & Norheim, Frode Amador [Show all 7 contributors for this article] (2024). Intra-Individual Variations in How Insulin Sensitivity Responds to Long-Term Exercise: Predictions by Machine Learning Based on Large-Scale Serum Proteomics. Metabolites. 14(6). doi: 10.3390/metabo14060335. Full text in Research Archive Show summary

  Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes.

• Pietzner, Maik; Uluvar, Burulca; Kolnes, Kristoffer Jensen; Jeppesen, Per Bendix; Frivold, Victoria & Skattebo, Øyvind [Show all 14 contributors for this article] (2024). Systemic proteome adaptions to 7-day complete caloric restriction in humans. Nature Metabolism. 6, p. 764–777. doi: 10.1038/s42255-024-01008-9. Full text in Research Archive Show summary

  Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.

• Guo, Shuai; Kolan, Shrikant; Li, Gaoyang; Hammarström, Clara Louise; Grimolizzi, Franco & Stuhr, Linda Elin Birkhaug [Show all 7 contributors for this article] (2024). Reduced EO771-induced tumour growth and increased overall-survival of mice ablated for immune cell-specific catalytic subunit Cβ2 of protein kinase A. Immunology Letters. ISSN 0165-2478. 268. doi: 10.1016/j.imlet.2024.106884. Full text in Research Archive Show summary

  Ablation of the immune-specific catalytic subunit Cβ2 of protein kinase A is associated with a proinflammatory phenotype and increased sensitivity to autoimmunity in mice. Here we show that tumour growth of the adenocarcinoma cell line EO771 in the breast and in the lung after injection into the mammary fat pad and tail vein, respectively, was significantly reduced in mice ablated for Cβ2 compared to wild-type mice. In both cases, the breast and lung tumours showed increased infiltration of immune cells in the mice lacking Cβ2 compared to wild-type mice. Despite this, it appeared that solid tissue- versus intravenously injected EO771 cells evoked different immune responses. This was reflected by significantly increased levels of splenic proinflammatory immune cells and circulating cytokines in Cβ2 ablated mice carrying breast- but not the lung tumours. Moreover, Cβ2 ablated mice injected with EO771 cells showed increased overall survival compared to wild-type mice. Taken together, our results suggest for a role for immune cell-specific Cβ2 in protecting against tumour growth induced by EO771 cells in mice that is reflected in improved overall survival.

• Lee-Ødegård, Sindre; Gundersen, Thomas Erik & Drevon, Christian André (2024). Effect of a plant extract of fenugreek (Trigonella foenum-graecum) on testosterone in blood plasma and saliva in a double blind randomized controlled intervention study. PLOS ONE. 19(9). doi: 10.1371/journal.pone.0310170. Full text in Research Archive Show summary

  Many aging men experience reduced energy and libido related to non-optimal testosterone levels. We conducted a randomized double-blind trial with TrigozimR fenugreek extract to assess impact on plasma and saliva testosterone, and some subjective effects. 95 men (40-80y) completed a 12-week intervention, taking 3 tablets daily with 0 mg (placebo; n = 22), 600 mg (n = 21), 1200 mg (n = 25) and1800 mg (n = 27) fenugreek extract and essential nutrients. Samples were collected at weeks 0, 2, 6, and 12. Participants answered a pre- and post-intervention questionnaire on lifestyle and libido. We measured total testosterone (HPLC-MS/MS) and sex hormone binding globulin (ELISA), calculated free testosterone index (FTI), and measured saliva testosterone. Plasma total testosterone and FTI increased after any dose of TrigozimR vs. baseline (13.0%, p = 1.0x10-4 and 16.3%, p = 6.2x10-6), but not vs. placebo (9.0%, p = 0.122 and 11.3% p = 0.059). 1800 mg TrigozimR resulted in 12.2% increased FTI (p = 0.025). Saliva testosterone concentration increased after any dose of TrigozimR vs. baseline (31.1%, p = 2.3x10-4) and vs. placebo (37.2%, p = 0.042). 1800 mg TrigozimR for 12 weeks resulted in 19.6% (p = 0.006) increased saliva testosterone. Compliance was confirmed by enhanced plasma concentration of 25-hydroxy vitamin D3. We observed no subjective effects or side-effects of TrigozimR. TrigozimR increased saliva and plasma testosterone concentration during intervention but only for saliva vs. placebo. Saliva may be preferred for measuring free testosterone due to no protein-bound testosterone.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2024). The association between body mass index and vulvar and vaginal cancer incidence: findings from a large Norwegian cohort study. Cancer Causes and Control. ISSN 0957-5243. 36, p. 191–198. doi: 10.1007/s10552-024-01930-z. Full text in Research Archive Show summary

  Background There is limited evidence of potential associations between body mass index (BMI) and risk of vulvar and vaginal cancer. We explored these associations in a large cohort of Norwegian women. Methods The analytical dataset included 889,441 women aged 16–75 years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and vulvar and vaginal cancer incidence. Results During 30.1 million person-years of follow-up, 1748 incident vulvar and 408 incident vaginal cancer cases occurred. The HRs (95% CIs) for vulvar cancer for a BMI of 15- < 18.5, 18.5- < 25, 25- < 30, 30- < 35, ≥ 35 were 0.62 (0.38–1.01), 1.00 (reference), 1.23 (1.10–1.40), 1.43 (1.23–1.66) and 1.72 (1.35–2.20, ptrend < 0.001), and per 5 kg/m2 increment was 1.20 (1.13–1.26). The corresponding HRs (95% CIs) for vaginal cancer were 1.05 (0.52–2.15), 1.00, 0.89 (0.71–1.12), 0.95 (0.68–1.34), and 2.01 (1.29–3.13, ptrend < 0.001), respectively, and per 5 kg/m2 was 1.11 (0.99–1.25). The HR (95% CI) per 5 kg/m2 increase in BMI at ages 16–29 was 1.28 (1.07–1.54, n = 250 cases) for vulvar and 1.53 (1.11–2.11, n = 66 cases) for vaginal cancers. The HR (95% CI) per 5 kg/m2 for early-onset (< 50 years age at diagnosis) vulvar cancer was 0.92 (0.66–1.28, n = 87 cases) and 1.70 (1.05–2.76, n = 21 cases) for vaginal cancer. Conclusion These results further support the associations between higher BMI and increased risk of vulvar and vaginal cancers, with suggestive stronger associations between BMI in early adulthood for both cancers and for early-onset vaginal cancer. Further studies are needed to elucidate these findings and investigate the underlying mechanisms.

• Bobrovs, Raitis; Terentjeva, Svetlana; Olafsen, Ninni Elise; Dambrauskas, Zilvinas; Gulbinas, Antanas & Maimets, Toivo [Show all 10 contributors for this article] (2024). Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists. RSC Medicinal Chemistry. ISSN 2632-8682. doi: 10.1039/d4md00266k. Full text in Research Archive
• Llorente, Alicia; Brokāne, Agnese; Mlynska, Agata; Puurand, Marju; Sagini, Krizia & Folkmane, Signe [Show all 16 contributors for this article] (2024). From sweat to hope: The role of exercise-induced extracellular vesicles in cancer prevention and treatment. Journal of Extracellular Vesicles. 13(8). doi: 10.1002/jev2.12500. Full text in Research Archive Show summary

  The benefits of regular physical exercise on cancer prevention, as well as reducing fatigue, treatment side effects and recurrence, and improving quality of life and over-all survival of cancer patients, are increasingly recognised. Initial studies showed that the concentration of extracellular vesicles (EVs) increases during physical activity and that EVs carry biologically active cargo. These EVs are released by blood cells, skeletal muscle and other organs involved in exercise, thus suggesting that EVs may mediate tissue crosstalk during exercise. This possibility triggered a great interest in the study of the roles of EVs in systemic adaptation to exercise and in their potential applications in the prevention and treatment of various diseases, including cancer. This review presents studies exploring the concentration and molecular cargo of EVs released during exercise. Furthermore, we discuss putative stimuli that may trigger EV release from various cell types, the biological functions and the impact of exercise-induced EVs on cancer development and progression. Understanding the interplay between exercise, EVs, and cancer biology may offer insights into novel therapeutic strategies and preventive measures for cancer.

• Aune, Dagfinn; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Skålhegg, Bjørn Steen & Mala, Tom [Show all 8 contributors for this article] (2024). Body mass index and penile cancer incidence: results from a Norwegian cohort study of 829,081 men. BMC Urology. 24(1), p. 1–6. doi: 10.1186/s12894-024-01636-z. Full text in Research Archive Show summary

  Background A few previous studies have suggested a possible association between adiposity and increased risk of penile cancer, however, the evidence is to date limited for this rare cancer. We investigated the association between body mass index (BMI) and penile cancer risk in a large Norwegian cohort. Methods The analyses included 829,081 men aged 16–75 years at baseline in 1963–1975. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between BMI and penile cancer incidence. Results A total of 725 incident penile cancer cases occurred during 25.6 million person-years of follow-up. Compared to men with BMI 18.5-<25, the HRs (95% CIs) of those with a BMI of 15-<18.5, 25-<30, and ≥ 30 were 0.45 (0.15–1.41), 1.14 (0.97–1.33) and 1.63 (1.20–2.22), respectively, and the HR was 1.26 (1.12–1.42) per 5 kg/m2 increase in BMI. When the obese category was further subdivided in grade 1 (BMI 30-<35) and grade 2 obesity (≥ 35), the respe

• Dalen, Knut Tomas & Li, Yuchuan (2024). Regulation of lipid droplets and cholesterol metabolism in adrenal cortical cells. Vitamines and Hormones. ISSN 0083-6729. 124, p. 79–136. doi: 10.1016/bs.vh.2023.06.007. Full text in Research Archive
• Nilsen, Lotte LK; Lambert, Max Norman Tandrup; Haubek, Dorte; Bastani, Nasser Ezzatkhah; Skålhegg, Bjørn Steen & Overgaard, Kristian [Show all 8 contributors for this article] (2024). The Effect of Alginate Encapsulated Plant-Based Carbohydrate and Protein Supplementation on Recovery and Subsequent Performance in Athletes. Nutrients. 16(3). doi: 10.3390/nu16030413. Full text in Research Archive Show summary

  The main purpose of this study was to investigate the effect of a novel alginate-encapsulated carbohydrate–protein (CHO–PRO ratio 2:1) supplement (ALG) on cycling performance. The ALG, designed to control the release of nutrients, was compared to an isocaloric carbohydrate-only control (CON). Alginate encapsulation of CHOs has the potential to reduce the risk of carious lesions. Methods: In a randomised cross-over clinical trial, 14 men completed a preliminary test over 2 experimental days separated by ~6 days. An experimental day consisted of an exercise bout (EX1) of cycling until exhaustion at W~73%, followed by 5 h of recovery and a subsequent time-to-exhaustion (TTE) performance test at W~65%. Subjects ingested either ALG (0.8 g CHO/kg/hr + 0.4 g PRO/kg/hr) or CON (1.2 g CHO/kg/hr) during the first 2 h of recovery. Results: Participants cycled on average 75.2 ± 5.9 min during EX1. Levels of plasma branched-chain amino acids decreased significantly after EX1, and increased significantly with the intake of ALG during the recovery period. During recovery, a significantly higher plasma insulin and glucose response was observed after intake of CON compared to ALG. Intake of ALG increased plasma glucagon, free fatty acids, and glycerol significantly. No differences were found in the TTE between the supplements (p = 0.13) nor in the pH of the subjects’ saliva. Conclusions: During the ALG supplement, plasma amino acids remained elevated during the recovery. Despite the 1/3 less CHO intake with ALG compared to CON, the TTE performance was similar after intake of either supplement.

• Clauss, Matthieu; Bukhardt, Meike; Wøber, Sophie; Skålhegg, Bjørn Steen & Jensen, Jørgen (2024). Effect of five hours of mixed exercise on urinary nitrogen excretion in healthy moderate-to-well-trained young adults. Frontiers in Nutrition. 11. doi: 10.3389/fnut.2024.1345922. Full text in Research Archive Show summary

  Introduction: Carbohydrates and fats are the primary energy substrates during exercise, but proteins can also contribute. When proteins are degraded in the body, the amino groups are mainly converted to urea and excreted. Therefore, nitrogen excretion has been used as a marker of protein degradation, but a clear conclusion has yet to be reached on the effect of exercise on nitrogen excretion. Thus, we tested whether exercise increases nitrogen excretion. Methods: Fifteen young, healthy, moderate-to-well-trained participants (4 females, 11 males, VO2max 54.4 ± 1.7 mL·kg−1·min−1; mean ± SEM) participated in a randomized, balanced cross-over design investigation consisting of 1 day with 5 h of exercise (exercise day, EX) and 1 day with no exercise (control day, CON). The participants recorded their dietary intake the day before from 16:00 and throughout the intervention day. They then repeated these dietary intakes on the second trial day. A standardized lunch was provided on both days. In addition, participants were allowed to consume almost protein-free snacks in EX to ensure the same energy balance during both trial days. Urine was collected throughout the whole testing period, and urinary 3-methylhistidine (3-MH) excretion was measured to examine muscular catabolism. The sweat rate was calculated during the exercise period. Results and discussion: The urinary nitrogen and 3-MH excretions did not differ significantly between EX and CON (p = 0.764 and p = 0.953). The sweat rate was 2.55 ± 0.25 L in EX and 0.14 ± 0.15 L in CON (p 

• Olafsen, Ninni Elise; Das, Siddhartha; Gorrini, Chiara & Matthews, Jason (2024). Long-term exposure to BAY2416964 reduces proliferation, migration and recapitulates transcriptional changes induced by AHR loss in PyMT-induced mammary tumor cells. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1466658. Full text in Research Archive Show summary

  The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor which in certain cancer types drives pro-survival processes that facilitate tumorigenesis, malignant cell migration, invasion, and metastasis. Much of AHR’s pro-tumorigenic action is due to its activation by the oncometabolite, kynurenine. Because of this AHR antagonists are being actively investigated as new anti-tumor therapy. In this study we compared the effects of treatment with the AHR antagonists, BAY2416964 and GNF351, to that of AHR knockout in PyMT murine mammary cancer cells. BAY2416964 and GNF351 effectively inhibited kynurenine-dependent increases in Cyp1a1 and Cyp1b1 mRNA levels. CRISPR/Cas9-generated PyMT AhrKO cells exhibited reduced cell proliferation compared with controls, but treatment with 1 μM BAY2416964 for 96 h had no effect on the proliferation of wildtype cells. To further examine the differences between AHR knockout and short term BAY2416964, we generated long-term BAY2416964 (LT-BAY) cells by exposing wildtype cells to 1 μM BAY2416964 for at least 6 weeks. Similar to AhrKO cells, LT-BAY cells exhibited reduced cell proliferation and migration compared with wildtype cells. No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer.

• Chau, Khac Thanh Phong; Ryan, Elin; Dalen, Knut Tomas & Haugen, Fred (2024). Timing of acute cold exposure determines UCP1 and FGF21 expression - Possible interactions between the thermal environment, thermoregulatory responses, and peripheral clocks. Journal of Thermal Biology. ISSN 0306-4565. 124. doi: 10.1016/j.jtherbio.2024.103938. Full text in Research Archive Show summary

  Thermoregulation is synchronized across the circadian cycle to uphold thermal homeostasis. To test if time-of-day matters for the response to environmental cold exposure, mice were acclimated to thermoneutrality (27 °C) for 2 months were subjected acutely (8 h) to cold ambient conditions (15 °C), whereas controls were maintained at thermoneutral conditions. The thermal exposure was tested in separate groups (N = 8) at three distinct time-of-day periods: in the LIGHT phase (L); the DARK phase (D); and a mix of the two (D + L). The magnitude of UCP1 protein and mRNA induction in brown adipose tissue (BAT) in response to acute cold exposure was time-of-day sensitive, peaking in LIGHT, whereas lower induction levels were observed in D + L, and DARK. Plasma levels of FGF21 were induced 3-fold by acute cold exposure at LIGHT and D + L, compared to the time-matched thermoneutral controls, whereas cold in DARK did not cause a significant increase of FGF21 plasma levels. Cold exposure affected, in BAT, the temporal mRNA expression patterns of core circadian clock components: Bmal1, Clock, Per1, Per3, Cry1, Cry2 Nr1d1, and Nr1d2, but in the liver, none of the transcripts were modified. Behavioral assessment using the Thermal Gradient Test (TGT) showed that acute cold exposure reduced cold sensitivity in D + L, but not in DARK. RNA-seq analyses of somatosensory neurons in DRG highlighted the role of the core circadian components in these cells, as well as transcriptional changes due to acute cold exposure. This elucidates the sensory system as a gauge and potential regulator of thermoregulatory responses based on circadian physiology. In conclusion, acute cold exposure elicits time-of-day specific effects on thermoregulatory pathways, which may involve underlying changes in thermal perception. These results have implications for efforts aimed at reducing risks associated with the organization of shift work in cold environments.

• Seferi, Gezime; Mjønes, Harald Stranger; Havik, Mona; Reiersen, Herman; Dalen, Knut Tomas & Nordengen, Kaja [Show all 7 contributors for this article] (2024). Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise. Life Science Alliance (LSA). 7(10). doi: 10.26508/lsa.202302239. Full text in Research Archive Show summary

  Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.

• Li, Yanjiao; Wang, Yunhao; Vera-Rodriguez, Maria; Lindeman, Leif Christopher; Skuggen, Linda Ellevog & Rasmussen, Erik Magne Koscielniak [Show all 21 contributors for this article] (2023). Single-cell m6A mapping in vivo using picoMeRIP–seq. Nature Biotechnology. ISSN 1087-0156. doi: 10.1038/s41587-023-01831-7. Full text in Research Archive Show summary

  Abstract Current N 6 -methyladenosine (m 6 A) mapping methods need large amounts of RNA or are limited to cultured cells. Through optimized sample recovery and signal-to-noise ratio, we developed picogram-scale m 6 A RNA immunoprecipitation and sequencing (picoMeRIP–seq) for studying m 6 A in vivo in single cells and scarce cell types using standard laboratory equipment. We benchmark m 6 A mapping on titrations of poly(A) RNA and embryonic stem cells and in single zebrafish zygotes, mouse oocytes and embryos.

• Jersin, Regine Åsen; Tallapragada, Divya Sri; Skartveit, Linn; Bjune, Mona Synnøve; Muniandy, Maheswary & Lee-Ødegård, Sindre [Show all 16 contributors for this article] (2023). Impaired Adipocyte SLC7A10 Promotes Lipid Storage in Association With Insulin Resistance and Altered BCAA Metabolism. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 108(9), p. 2217–2229. doi: 10.1210/clinem/dgad148. Full text in Research Archive Show summary

  Context The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity. Objective We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites. Methods In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts. Results SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB. Conclusion Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.

• Das, Siddhartha; Somisetty, Venkata Satheesh; Ulven, Stine Marie & Matthews, Jason (2023). Resveratrol and 3,3′-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells. International Journal of Molecular Sciences. ISSN 1661-6596. 24(19). doi: 10.3390/ijms241914578. Full text in Research Archive Show summary

  Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3′diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes.

• Saeed, Usman; Nordsletten, Marie Wiborg; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Cancer risk and survival according to body mass index in hepatobiliary malignancies: a nationwide registry-based cohort study. HPB. ISSN 1365-182X. 25(11), p. 1382–1392. doi: 10.1016/j.hpb.2023.07.882. Full text in Research Archive Show summary

  Background The aim of this study was to explore the associations between BMI and cancer of the liver, bile ducts, and gallbladder. Methods A registry-based cohort study was performed by linking data from several national registries in Norway. Results The cohort comprised 1 723 692 individuals including 4768 hepatobiliary cancer cases during 55 743 509 person-years of follow-up. In men, we found increased risk of cancer per 5 kg/m2 BMI increase for hepatocellular carcinoma and extrahepatic cholangiocarcinoma. In women there was increased risk of extrahepatic cholangiocarcinoma and gallbladder cancer. Women with high BMI in early adulthood had increased risk of intrahepatic cholangiocarcinoma. Reduced cancer-specific survival was found for all hepatobiliary malignancies in women with overweight and obesity. In men, reduced survival was observed in individuals with obesity for all hepatobiliary cancers, except gallbladder cancer. Increased risk of cancer-death per 5 kg/m2 BMI increase was found for hepatocellular carcinoma, intra-, and extrahepatic cholangiocarcinoma in women. For men, 5 kg/m2 BMI increase was positively associated with cancer-death from intrahepatic cholangiocarcinoma. Discussion This study supports the notion of an increased risk of hepatobiliary cancers with increasing BMI, with sex and age variations. The findings also suggest a higher risk of cancer-death with increasing BMI.

• Bodin, Johanna Eva; Aakre, Inger; Alexander, Jan; Mangschou, Bente; Parr, Christine Louise & Andersen, Lene Frost [Show all 15 contributors for this article] (2023). Risk assessment of hyaluronic acid in food supplements. VKM Report. 13, p. 1–70. Full text in Research Archive Show summary

  Hyaluronic acid (HA) is a high-molecular-mass polysaccharide, that is endogenously produced and present in connective tissue, synovial fluid, intraoccular fluid, and skin. The basic unit of the HA polymer consists of D-glucuronic acid and N-acetyl-D-glucosamine. The Norwegian Food Safety Authority has requested VKM to evaluate the risk of adverse effects related to daily intake of food supplements with 150 mg, 120 mg, 64 mg, and 48 mg HA. Exposure from other sources of HA (food, cosmetics, and different medical applications) is not estimated.

• Binnewies, Julia; Nawijn, Laura; Brandmaier, Andreas M.; Baaré, William F.C.; Boraxbekk, Carl-Johan & Demnitz, Naiara [Show all 15 contributors for this article] (2023). Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium. Brain Research Bulletin. ISSN 0361-9230. 200. doi: 10.1016/j.brainresbull.2023.110692. Full text in Research Archive Show summary

  Background Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. Methods We included 3838 participants aged 18–90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. Results High alcohol use was associated with lower hippocampal volume (r = −0.10, p = 0.021), and overweight/obesity with lower total GMV (r = −0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = −0.08, p = 0.001), but not hippocampal volume (r = −0.01, p = 0.625). Conclusions This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.

• Bartkeviciene, Arenida; Jasukaitiene, Aldona; Zievyte, Inga; Stukas, Darius; Ivanauskiene, Sandra & Urboniene, Daiva [Show all 12 contributors for this article] (2023). Association between AHR Expression and Immune Dysregulation in Pancreatic Ductal Adenocarcinoma: Insights from Comprehensive Immune Profiling of Peripheral Blood Mononuclear Cells. Cancers. 15(18). doi: 10.3390/cancers15184639. Full text in Research Archive Show summary

  Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), has an immune suppressive environment that allows tumour cells to evade the immune system. The aryl-hydrocarbon receptor (AHR) is a transcription factor that can be activated by certain exo/endo ligands, including kynurenine (KYN) and other tryptophan metabolites. Once activated, AHR regulates the expression of various genes involved in immune responses and inflammation. Previous studies have shown that AHR activation in PDAC can have both pro-tumorigenic and anti-tumorigenic effects, depending on the context. It can promote tumour growth and immune evasion by suppressing anti-tumour immune responses or induce anti-tumour effects by enhancing immune cell function. In this study involving 30 PDAC patients and 30 healthy individuals, peripheral blood samples were analysed. PDAC patients were categorized into Low (12 patients) and High/Medium (18 patients) AHR groups based on gene expression in peripheral blood mononuclear cells (PBMCs). The Low AHR group showed distinct immune characteristics, including increased levels of immune-suppressive proteins such as PDL1, as well as alterations in lymphocyte and monocyte subtypes. Functional assays demonstrated changes in phagocytosis, nitric oxide production, and the expression of cytokines IL-1, IL-6, and IL-10. These findings indicate that AHR’s expression level has a crucial role in immune dysregulation in PDAC and could be a potential target for early diagnostics and personalised therapeutics.

• gjølberg, torleif; Wik, Jonas Aakre; Johannessen, Hanna; Krüger, Stig; Bassi, Nicola & Christopoulos, Panagiotis [Show all 15 contributors for this article] (2023). Antibody blockade of Jagged1 attenuates choroidal neovascularization. Nature Communications. 14(1). doi: 10.1038/s41467-023-38563-w. Full text in Research Archive Show summary

  Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.

• Meen, Astri Jeanette; Doncheva, Atanaska Ivanova; Böttcher, Yvonne; Dankel, Simon N; Hoffmann, Anne & Blüher, Matthias [Show all 16 contributors for this article] (2023). Obesity Is Associated with Distorted Proteoglycan Expression in Adipose Tissue. International Journal of Molecular Sciences. ISSN 1661-6596. 24(8). doi: 10.3390/ijms24086884. Full text in Research Archive Show summary

  Proteoglycans are central components of the extracellular matrix (ECM) and binding partners for inflammatory chemokines. Morphological differences in the ECM and increased inflammation are prominent features of the white adipose tissues in patients with obesity. The impact of obesity and weight loss on the expression of specific proteoglycans in adipose tissue is not well known. This study aimed to investigate the relationship between adiposity and proteoglycan expression. We analyzed transcriptomic data from two human bariatric surgery cohorts. In addition, RT-qPCR was performed on adipose tissues from female and male mice fed a high-fat diet. Both visceral and subcutaneous adipose tissue depots were analyzed. Adipose mRNA expression of specific proteoglycans, proteoglycan biosynthetic enzymes, proteoglycan partner molecules, and other ECM-related proteins were altered in both human cohorts. We consistently observed more profound alterations in gene expression of ECM targets in the visceral adipose tissues after surgery (among others VCAN (p = 0.000309), OGN (p = 0.000976), GPC4 (p = 0.00525), COL1A1 (p = 0.00221)). Further, gene analyses in mice revealed sex differences in these two tissue compartments in obese mice. We suggest that adipose tissue repair is still in progress long after surgery, which may reflect challenges in remodeling increased adipose tissues. This study can provide the basis for more mechanistic studies on the role of proteoglycans in adipose tissues in obesity.

• Li, Yuchuan; Amrutkar, Manoj; Finstadsveen, Anette V.; Dalen, Knut Tomas; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2023). Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells. Cancer Cell International. 23. doi: 10.1186/s12935-023-03138-8. Full text in Research Archive Show summary

  Background Despite therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Metabolic reprogramming is increasingly recognized as a key contributor to tumor progression and therapy resistance in PDAC. One of the main metabolic changes essential for tumor growth is altered cholesterol flux. Targeting cholesterol flux appears an attractive therapeutic approach, however, the complex regulation of cholesterol balance in PDAC cells remains poorly understood. Methods The lipid content in human pancreatic duct epithelial (HPDE) cells and human PDAC cell lines (BxPC-3, MIA PaCa-2, and PANC-1) was determined. Cells exposed to eight different inhibitors targeting different regulators of lipid flux, in the presence or absence of oleic acid (OA) stimulation were assessed for changes in viability, proliferation, migration, and invasion. Intracellular content and distribution of cholesterol was assessed. Lastly, proteome profiling of PANC-1 exposed to the sterol O-acyltransferase 1 (SOAT1) inhibitor avasimibe, in presence or absence of OA, was performed. Results PDAC cells contain more free cholesterol but less cholesteryl esters and lipid droplets than HPDE cells. Exposure to different lipid flux inhibitors increased cell death and suppressed proliferation, with different efficiency in the tested PDAC cell lines. Avasimibe had the strongest ability to suppress proliferation across the three PDAC cell lines. All inhibitors showing cell suppressive effect disturbed intracellular cholesterol flux and increased cholesterol aggregation. OA improved overall cholesterol balance, reduced free cholesterol aggregation, and reversed cell death induced by the inhibitors. Treatment with avasimibe changed the cellular proteome substantially, mainly for proteins related to biosynthesis and metabolism of lipids and fatty acids, apoptosis, and cell adhesion. Most of these changes were restored by OA. Conclusions The study reveals that disturbing the cholesterol flux by inhibiting the actions of its key regulators can yield growth suppressive effects on PDAC cells. The presence of fatty acids restores intracellular cholesterol balance and abrogates the alternations induced by cholesterol flux inhibitors. Taken together, targeting cholesterol flux might be an attractive strategy to develop new therapeutics against PDAC. However, the impact of fatty acids in the tumor microenvironment must be taken into consideration.

• Rasmussen, Marit; Alvik, Karoline; Kannen, Vinicius; Olafsen, Ninni Elise; Erlingsson, Linnea Anna Margareta & Grimaldi, Giulia [Show all 9 contributors for this article] (2023). Loss of PARP7 Increases Type I Interferon Signaling in EO771 Breast Cancer Cells and Prevents Mammary Tumor Growth by Increasing Antitumor Immunity. Cancers. 15(14). doi: 10.3390/cancers15143689. Full text in Research Archive Show summary

  PARP7 is a member of the ADP-ribosyltransferase diphtheria toxin-like (ARTD) family and acts as a repressor of type I interferon (IFN) signaling. PARP7 inhibition causes tumor regression by enhancing antitumor immunity, which is dependent on the stimulator of interferon genes (STING) pathway, TANK-binding kinase 1 (TBK1) activity, and cytotoxic CD8+ T cells. To better understand PARP7′s role in cancer, we generated and characterized PARP7 knockout (Parp7KO) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant Parp7H532A mice. Loss of PARP7 expression or inhibition of its activity increased type I IFN signaling, as well as the levels of interferon-stimulated gene factor 3 (ISGF3) and specifically unphosphorylated-ISGF3 regulated target genes. This was partly because PARP7′s modification of the RelA subunit of nuclear factor κ-B (NF-κB). PARP7 loss had no effect on tumor growth in immunodeficient mice. In contrast, injection of wildtype cells into Parp7H532A mice resulted in smaller tumors compared with cells injected into Parp7+/+ mice. Parp7H532A mice injected with Parp7KO cells failed to develop tumors and those that developed regressed. Our data highlight the importance of PARP7 in the immune cells and further support targeting PARP7 for anticancer therapy.

• Doncheva, Atanaska Ivanova; Li, Yuchuan; Khanal, Prabhat; Hjorth, Marit; Kolset, Svein Olav & Norheim, Frode Amador [Show all 8 contributors for this article] (2023). Altered hepatic lipid droplet morphology and lipid metabolism in fasted Plin2-null mice. Journal of Lipid Research. ISSN 0022-2275. 64(12). doi: 10.1016/j.jlr.2023.100461. Full text in Research Archive Show summary

  Perilipin 2 (Plin2) binds to the surface of hepatic lipid droplets (LDs) with expression levels that correlate with triacylglyceride (TAG) content. We investigated if Plin2 is important for hepatic LD storage in fasted or high-fat diet-induced obese Plin2+/+ and Plin2−/− mice. Plin2−/− mice had comparable body weights, metabolic phenotype, glucose tolerance, and circulating TAG and total cholesterol levels compared with Plin2+/+ mice, regardless of the dietary regime. Both fasted and high-fat fed Plin2−/− mice stored reduced levels of hepatic TAG compared with Plin2+/+ mice. Fasted Plin2−/− mice stored fewer but larger hepatic LDs compared with Plin2+/+ mice. Detailed hepatic lipid analysis showed substantial reductions in accumulated TAG species in fasted Plin2−/− mice compared with Plin2+/+ mice, whereas cholesteryl esters and phosphatidylcholines were increased. RNA-Seq revealed minor differences in hepatic gene expression between fed Plin2+/+ and Plin2−/− mice, in contrast to marked differences in gene expression between fasted Plin2+/+ and Plin2−/− mice. Our findings demonstrate that Plin2 is required to regulate hepatic LD size and storage of neutral lipid species in the fasted state, while its role in obesity-induced steatosis is less clear.

• Pejšková, Lucie; Rønning, Sissel Beate; Kent, Matthew Peter; Solberg, Nina; Høst, Vibeke & To, Thu-Hien [Show all 13 contributors for this article] (2023). Characterization of wooden breast myopathy: a focus on syndecans and ECM remodeling. Frontiers in Physiology. 14, p. 1–17. doi: 10.3389/fphys.2023.1301804. Full text in Research Archive Show summary

  The skeletal muscle deformity of commercial chickens (Gallus gallus), known as the wooden breast (WB), is associated with fibrotic myopathy of unknown etiology. For future breeding strategies and genetic improvements, it is essential to identify the molecular mechanisms underlying the phenotype. The pathophysiological hallmarks of WB include severe skeletal muscle fibrosis, inflammation, myofiber necrosis, and multifocal degeneration of muscle tissue. The transmembrane proteoglycans syndecans have a wide spectrum of biological functions and are master regulators of tissue homeostasis. They are upregulated and shed (cleaved) as a regulatory mechanism during tissue repair and regeneration. During the last decades, it has become clear that the syndecan family also has critical functions in skeletal muscle growth, however, their potential involvement in WB pathogenesis is unknown.

• Pfabigan, Daniela M.; Frogner, Erik Rimestad; Schéle, Erik; Thorsby, Per Medbøe; Skålhegg, Bjørn Steen & Dickson, Suzanne L. [Show all 7 contributors for this article] (2023). Ghrelin is related to lower brain reward activation during touch. Psychophysiology. ISSN 0048-5772. 61(2). doi: 10.1111/psyp.14443. Full text in Research Archive Show summary

  The gut hormone ghrelin drives food motivation and increases food intake, but it is also involved in the anticipation of and response to rewards other than food. This pre-registered study investigated how naturally varying ghrelin concentrations affect the processing of touch as a social reward in humans. Sixty-seven volunteers received slow caressing touch (so-called CT-targeted touch) as a social reward and control touch on their shins during 3T functional imaging on two test days. On one occasion, participants were fasted, and on another, they received a meal. On each occasion, plasma ghrelin was measured at three time points. All touch was rated as more pleasant after the meal, but there was no association between ghrelin concentrations and pleasantness. CT-targeted touch was rated as the most pleasant and activated somatosensory and reward networks (whole brain). A region-of-interest in the right medial orbitofrontal cortex (mOFC) showed lower activation during all touches, the higher the ghrelin concentrations were. During CT-targeted touch, a larger satiety response (ghrelin decrease after the meal) was associated with higher mOFC activation, and this mOFC activation was associated with higher experienced pleasantness. Overall, higher ghrelin concentrations appear to be related to a lower reward value for touch. Ghrelin may reduce the value of social stimuli, such as touch, to promote food search and intake in a state of low energy. This suggests that the role of ghrelin goes beyond assigning value to food reward.

• Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F. C. & Bartrés-Faz, David [Show all 24 contributors for this article] (2023). No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy. Nature Human Behaviour. 7, p. 2008–2022. doi: 10.1038/s41562-023-01707-5. Full text in Research Archive Show summary

  Abstract Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration—which is shorter than current recommendations.

• Stukas, Darius; Jasukaitiene, Aldona; Bartkeviciene, Arenida; Matthews, Jason; Maimets, Toivo & Teino, Indrek [Show all 9 contributors for this article] (2023). Targeting AHR Increases Pancreatic Cancer Cell Sensitivity to Gemcitabine through the ELAVL1-DCK Pathway. International Journal of Molecular Sciences. ISSN 1661-6596. 24(17). doi: 10.3390/ijms241713155. Full text in Research Archive Show summary

  The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. AHR and ELAVL1 genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and AHR mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of AHR diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway.

• Rundle, Milena; Fiamoncini, Jarlei; Thomas, E Louise; Wopereis, Suzan; Afman, Lydia A. & Brennan, Lorraine [Show all 15 contributors for this article] (2023). Diet-induced Weight Loss and Phenotypic Flexibility Among Healthy Overweight Adults: A Randomized Trial. American Journal of Clinical Nutrition. ISSN 0002-9165. 118(3), p. 591–604. doi: 10.1016/j.ajcnut.2023.07.002. Full text in Research Archive Show summary

  Background The capacity of an individual to respond to changes in food intake so that postprandial metabolic perturbations are resolved, and metabolism returns to its pre-prandial state, is called phenotypic flexibility. This ability may be a more important indicator of current health status than metabolic markers in a fasting state. Aim In this parallel randomized controlled trial study, an energy-restricted healthy diet and 2 dietary challenges were used to assess the effect of weight loss on phenotypic flexibility. Methods Seventy-two volunteers with overweight and obesity underwent a 12-wk dietary intervention. The participants were randomized to a weight loss group (WLG) with 20% less energy intake or a weight-maintenance group (WMG). At weeks 1 and 12, participants were assessed for body composition by MRI. Concurrently, markers of metabolism and insulin sensitivity were obtained from the analysis of plasma metabolome during 2 different dietary challenges—an oral glucose tolerance test (OGTT) and a mixed-meal tolerance test. Results Intended weight loss was achieved in the WLG (−5.6 kg, P < 0.0001) and induced a significant reduction in total and regional adipose tissue as well as ectopic fat in the liver. Amino acid-based markers of insulin action and resistance such as leucine and glutamate were reduced in the postprandial phase of the OGTT in the WLG by 11.5% and 28%, respectively, after body weight reduction. Weight loss correlated with the magnitude of changes in metabolic responses to dietary challenges. Large interindividual variation in metabolic responses to weight loss was observed. Conclusion Application of dietary challenges increased sensitivity to detect metabolic response to weight loss intervention. Large interindividual variation was observed across a wide range of measurements allowing the identification of distinct responses to the weight loss intervention and mechanistic insight into the metabolic response to weight loss.

• Wang, Yunhao; Li, Yanjiao; Skuland, Trine; Zhou, Chengjie; Li, Aifu & Hashim, Adnan [Show all 13 contributors for this article] (2023). The RNA m6A landscape of mouse oocytes and preimplantation embryos. Nature Structural & Molecular Biology. ISSN 1545-9993. 30(5), p. 703–709. doi: 10.1038/s41594-023-00969-x. Full text in Research Archive Show summary

  Despite the significance of N6-methyladenosine (m6A) in gene regulation, the requirement for large amounts of RNA has hindered m6A profiling in mammalian early embryos. Here we apply low-input methyl RNA immunoprecipitation and sequencing to map m6A in mouse oocytes and preimplantation embryos. We define the landscape of m6A during the maternal-to-zygotic transition, including stage-specifically expressed transcription factors essential for cell fate determination. Both the maternally inherited transcripts to be degraded post fertilization and the zygotically activated genes during zygotic genome activation are widely marked by m6A. In contrast to m6A-marked zygotic ally-activated genes, m6A-marked maternally inherited transcripts have a higher tendency to be targeted by microRNAs. Moreover, RNAs derived from retrotransposons, such as MTA that is maternally expressed and MERVL that is transcriptionally activated at the two-cell stage, are largely marked by m6A. Our results provide a foundation for future studies exploring the regulatory roles of m6A in mammalian early embryonic development.

• Hope, Sigrun; Nærland, Terje; Kolset, Svein Olav; Ueland, Thor; Andreassen, Ole & Nordstrøm, Marianne (2023). Systemic immune profile in Prader-Willi syndrome: elevated matrix metalloproteinase and myeloperoxidase and reduced macrophage inhibitory factor. Orphanet Journal of Rare Diseases. 18(1), p. 185–185. doi: 10.1186/s13023-023-02730-5. Full text in Research Archive Show summary

  Background - Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence suggests that inflammation is implicated in the pathogenesis. Here we investigated CVD related immune markers to shed light on pathogenetic mechanisms.<p> <p>Methods - We performed a cross-sectional study with 22 participants with PWS and 22 healthy controls (HC), and compared levels of 21 inflammatory markers that reflect activity in different aspects of CVD related immune pathways and analyzed their association with clinical CVD risk factors.<p> <p>Results - Serum levels of matrix metalloproteinase 9 (MMP-9) was (median (range)) 121 (182) ng/ml in PWS versus 44 (51) ng/ml in HC, p = 1 × 10-9), myeloperoxidase (MPO) was 183 (696) ng/ml versus 65 (180) ng/ml, p = 1 × 10-5) and macrophage inhibitory factor (MIF) was 46 (150) ng/ml versus 121 (163) ng/ml (p = 1 × 10-3), after adjusting for age and sex. Also other markers tended to be elevated (OPG, sIL2RA, CHI3L1, VEGF) but not significantly after Bonferroni correction (p > 0.002). As expected PWS had higher body mass index, waist circumference, leptin, C-reactive protein, glycosylated hemoglobin (HbA1c), VAI and cholesterol, but MMP-9, MPO and MIF remained significantly different in PWS after adjustment for these clinical CVD risk factors.<p> <p>Conclusion - PWS had elevated levels of MMP-9 and MPO and of reduced levels of MIF, which were not secondary to comorbid CVD risk factors. This immune profile suggests enhanced monocyte/neutrophil activation, impaired macrophage inhibition with enhanced extracellular matrix remodeling. These findings warrant further studies targeting these immune pathways in PWS.

• Sollie, Ove; Clauss, Matthieu; Jeppesen, Per Bendix; Tangen, Daniel S.; Johansen, Egil Ivar & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Similar performance after intake of carbohydrate plus whey protein and carbohydrate only in the early phase after non-exhaustive cycling. Scandinavian Journal of Medicine & Science in Sports. ISSN 0905-7188. 33(7), p. 1091–1103. doi: 10.1111/sms.14364. Full text in Research Archive Show summary

  Aim: The aim of the present study was to compare performance 5 h after a 90-min endurance training session when either carbohydrate only or carbohydrate with added whey hydrolysate or whey isolate was ingested during the first 2 h of the recovery period. Methods: Thirteen highly trained competitive male cyclists completed three exercise and diet interventions (double-blinded, randomized, crossover design) separated by 1 week. The 90-min morning session (EX1) included a 60 min time-trial (TT60). Immediately and 1 h after exercise, participants ingested either (1) 1.2 g carbohydrate∙kg−1∙h−1 (CHO), (2) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g isolate whey protein∙kg−1∙h−1 (ISO) or (3) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g hydrolysate whey protein∙kg−1∙h−1 (HYD). Additional intakes were identical between interventions. After 5 h of recovery, participants completed a time-trial performance (TTP) during which a specific amount of work was performed. Blood and urine were collected throughout the day. Results: TTP did not differ significantly between dietary interventions (CHO: 43:54 ± 1:36, ISO: 46:55 ± 2:32, HYD: 44:31 ± 2:01 min). Nitrogen balance during CHO was lower than ISO (p < 0.0001) and HYD (p < 0.0001), with no difference between ISO and HYD (p = 0.317). In recovery, the area under the curve for blood glucose was higher in CHO compared to ISO and HYD. HR, VO2, RER, glucose, and lactate during EX2 were similar between interventions. Conclusion: Performance did not differ after 5 h of recovery whether carbohydrate only or isocaloric carbohydrate plus protein was ingested during the first 2 h. Correspondingly, participants were not in negative nitrogen balance in any dietary intervention.

• Nordsletten, Marie Wiborg; Saeed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2023). Body mass index and its association with 22 cancer types: a Norwegian cohort study of 481 202 cancer cases. Acta Oncologica. ISSN 0284-186X. 62(10), p. 1273–1278. doi: 10.1080/0284186X.2023.2258443. Full text in Research Archive
• Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F C & Bartrés-Faz, David [Show all 21 contributors for this article] (2023). Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers. Journal of Neuroscience. ISSN 0270-6474. 43(28), p. 5241–5250. doi: 10.1523/JNEUROSCI.2330-22.2023. Full text in Research Archive Show summary

  Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20–89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep &lt;6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems ( n = 1742) and participants sleeping the recommended 7–8 h ( n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

• Hindar, Kjetil; Bodin, Johanna Eva; Duale, Nur; Jevnaker, Anne-Marthe Ganes; Garseth, Åse Helen & Malmstrøm, Martin [Show all 15 contributors for this article] (2023). Environmental risk assessment of genetically modified sterile VIRGIN® Atlantic salmon for use in research trials in aquaculture sea-cages. VKM Report. 2023:20, p. 1–94. Full text in Research Archive Show summary

  One of the substantial environmental challenges posed by the aquaculture industry is the escape of farmed Atlantic salmon (Salmo salar), which can mate with wild Atlantic salmon and alter the genetic composition of the wild populations. One potential solution to mitigate this issue is the cultivation of sterile salmon in aquaculture. Atlantic salmon can be made sterile by pressure or temperature treatment of newly fertilized eggs to produce triploids, which are functionally sterile due to their unpaired chromosomes. However, these triploids often perform poorly on commercial fish farms and the production of triploid salmon in Norway is put on hold due to welfare issues of the fish.

• Pourteymour, Shirin; Drevon, Christian André; Dalen, Knut Tomas & Norheim, Frode Amador (2023). Mechanisms Behind NAFLD: a System Genetics Perspective. Current Atherosclerosis Reports. ISSN 1523-3804. 25(11), p. 869–878. doi: 10.1007/s11883-023-01158-3. Full text in Research Archive
• Moore, Timothy M.; Lee-Ødegård, Sindre; Olsen, Thomas; Morselli, Marco; Strumwasser, Alexander R. & Lin, Amanda J. [Show all 40 contributors for this article] (2023). Conserved multi-tissue transcriptomic adaptations to exercise training in humans and mice. Cell reports. 42(5). doi: 10.1016/j.celrep.2023.112499. Full text in Research Archive Show summary

  Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.

• Lee-Ødegård, Sindre; Olsen, Thomas; Norheim, Frode Amador; Drevon, Christian A & Birkeland, Kåre Inge (2022). Potential Mechanisms for How Long-Term Physical Activity May Reduce Insulin Resistance. Metabolites. 12(3)(208). doi: 10.3390/metabo12030208. Full text in Research Archive Show summary

  Insulin became available for the treatment of patients with diabetes 100 years ago, and soon thereafter it became evident that the biological response to its actions differed markedly between individuals. This prompted extensive research into insulin action and resistance (IR), resulting in the universally agreed fact that IR is a core finding in patients with type 2 diabetes mellitus (T2DM). T2DM is the most prevalent form of diabetes, reaching epidemic proportions worldwide. Physical activity (PA) has the potential of improving IR and is, therefore, a cornerstone in the prevention and treatment of T2DM. Whereas most research has focused on the acute effects of PA, less is known about the effects of long-term PA on IR. Here, we describe a model of potential mechanisms behind reduced IR after long-term PA to guide further mechanistic investigations and to tailor PA interventions in the therapy of T2DM. The development of such interventions requires knowledge of normal glucose metabolism, and we briefly summarize an integrated physiological perspective on IR. We then describe the effects of long-term PA on signaling molecules involved in cellular responses to insulin, tissue-specific functions, and whole-body IR.

• Wik, Jonas Aakre; Chowdhury, Azazul Islam; Kolan, Shrikant; Bastani, Nasser Ezzatkhah; Li, Gaoyang & Alam, Kazi [Show all 8 contributors for this article] (2022). Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia. Biochemical Journal. ISSN 0264-6021. 479(11), p. 1221–1235. doi: 10.1042/BCJ20220144. Full text in Research Archive Show summary

  To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1–4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.

• Saaed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Møller, Bjørn; Mala, Tom & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2022). Body mass index and pancreatic adenocarcinoma: A nationwide registry-based cohort study. Scandinavian Journal of Surgery. ISSN 1457-4969. 112(1), p. 11–21. doi: 10.1177/14574969221127530. Full text in Research Archive Show summary

  Background and objective:An association between body mass index (BMI) and pancreatic cancer is suggested in observational studies. However, further studies are required to substantiate available evidence. The aim of this study was to explore the association between BMI and pancreatic ductal adenocarcinoma (PDAC) risk, treatment, and mortality. Methods:A registry-based cohort study was performed by combining data from four registries in Norway. Baseline data were collected between 1963 and 1975 with follow-up data collected until 2018. Kaplan–Meier curves and multivariable Cox regressions were estimated. Chi-square tests were used to analyze differences between groups. Results:The study cohort consisted of 1,723,692 individuals. A total of 8973 PDAC cases were identified during 55,744,749 person-years of follow-up. A 5 kg/m2 increase in BMI was associated with an increased risk of PDAC if high BMI at young age (16–29 years) (hazard ratio (HR): 1.21, 95% confidence interval (CI): 1.13–1.31), both for men (HR: 1.30, 95% CI: 1.15–1.46) and women (HR: 1.16, 95% CI: 1.05–1.28). In men, there was a 52% increase in risk of early-onset PDAC (<age 50) (HR: 1.52, 95% CI: 1.13-2.03) with 5 kg/m2 increase in BMI. A total of 2645 individuals were diagnosed with stage 1–3 disease, of whom 1131 underwent curative surgery. In all, 49% of normal weight, 38% overweight, and 30% obese individuals with stage 1–3 PDAC underwent surgery with curative intent (p < 0.001). Cancer survival was lower in overweight and obese individuals for both sexes. Analysis adjusted for sex, age, and period of diagnosis confirmed increased risk of cancer death in obese individuals. Conclusion:This study suggests that increased BMI in young adults may increase the risk of PDAC, and higher BMI in men is associated with an increased risk of early onset PDAC (<age 50). Overweight and obese individuals were less likely to undergo curative surgery and obese individuals had a higher risk of cancer-related death.

• Doncheva, Atanaska Ivanova; Romero, Silvana Angelica Troncoso; Ramirez-Garrastacho, Manuel; Lee-Ødegård, Sindre; Kolnes, Kristoffer Jensen & Tangen, Daniel S. [Show all 11 contributors for this article] (2022). Extracellular vesicles and microRNAs are altered in response to exercise, insulin sensitivity and overweight. Acta Physiologica. ISSN 1748-1708. 236(4). doi: 10.1111/apha.13862. Full text in Research Archive Show summary

  Abstract: Extracellular vesicles induced by exercise have emerged as potential mediators of tissue crosstalk. Extracellular vesicles and their cargo miRNAs have been linked to dysglycemia and obesity in animal models, but their role in humans is unclear. Aim: The aim of the study was to characterize the miRNA content in plasma extracellular vesicle isolates after acute and long-term exercise and to study associations between extracellular vesicle miRNAs, mRNA expression in skeletal muscle and adipose tissue, and cardiometabolic risk factors. Methods: Sedentary men with or without dysglycemia and overweight underwent an acute bicycle test and a 12-week exercise intervention with extensive metabolic phenotyping. Gene expression in m. vastus lateralis and subcutaneous adipose tissue was measured with RNA sequencing. Extracellular vesicles were purified from plasma with membrane affinity columns or size exclusion chromatography. Results: Extracellular vesicle miRNA profiling revealed a transient increase in the number of miRNAs after acute exercise. We identified miRNAs, such as miR-652-3p, that were associated to insulin sensitivity and adiposity. By performing explorative association analyses, we identified two miRNAs, miR-32-5p and miR-339-3p, that were strongly correlated to an adipose tissue macrophage signature. Conclusion: Numerous miRNAs in plasma extracellular vesicle isolates were increased by exercise, and several miRNAs correlated to insulin sensitivity and adiposity. Our findings warrant future studies to characterize exercise-induced extracellular vesicles and cargo miRNA to clarify where exercise-induced extracellular vesicles originate from, and to determine whether they influence metabolic health or exercise adaptation.

• Vázquez-Gómez, Gerardo; Karasová, Martina; Tylichová, Zuzana; Kabátková, Markéta; Hampl, Aleš & Matthews, Jason [Show all 10 contributors for this article] (2022). Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling. Cells. 11(4). doi: 10.3390/cells11040707. Full text in Research Archive Show summary

  Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.

• Alvik, Karoline; Shao, Peng; Hutin, David; Baglole, Carolyn J.; Grant, Denis M & Matthews, Jason (2022). Increased sensitivity to chemically induced colitis in mice harboring a DNA-binding deficient aryl hydrocarbon receptor. Toxicological Sciences. ISSN 1096-6080. 191(2), p. 321–331. doi: 10.1093/toxsci/kfac132. Full text in Research Archive Show summary

  Abstract The aryl hydrocarbon receptor (AHR), a transcription factor best known for mediating toxic responses of environmental pollutants, also integrates metabolic signals to promote anti-inflammatory responses, intestinal homeostasis, and maintain barrier integrity. AHR regulates its target genes through direct DNA-binding to aryl hydrocarbon response elements (AHREs) but also through tethering to other transcription factors in a DNA-binding independent manner. However, it is not known if AHR’s anti-inflammatory role in the gut requires its ability to bind to AHREs. To test this, we determined the sensitivity of Ahrdbd/dbd mice, a genetically modified mouse line that express an AHR protein incapable of binding to AHREs, to dextran sulfate sodium (DSS)-induced colitis. Ahrdbd/dbd mice exhibited more severe symptoms of intestinal inflammation than Ahr+/+ mice. None of the Ahrdbd/dbd mice survived after the 5-day DSS followed by 7-day washout period. By day 6, the Ahrdbd/dbd mice had severe body weight loss, shortening of the colon, higher disease index scores, enlarged spleens, and increased expression of several inflammation genes, including interleukin 1b (Il-1b), Il-6, Il-17, C-x-c motif chemokine ligand 1 (Cxcl1), Cxcl2, Prostaglandin-endoperoxide synthase (Ptgs2), and lipocalin-2. Our findings show that AHR’s DNA-binding domain and ability to bind to AHREs are required to reduce inflammation, maintain a healthy intestinal environment, and protect against DSS-induced colitis.

• Sakita, Juliana Y.; Elias-Oliveira, Jefferson; Carlos, Daniela; Santos, Emerson de Souza; Almeida, Luciana Yamamoto & Malta, Tathiane M. [Show all 20 contributors for this article] (2022). Mast cell-T cell axis alters development of colitis-dependent and colitis-independent colorectal tumours: potential for therapeutically targeting via mast cell inhibition. Journal for ImmunoTherapy of Cancer (JITC). 10(10). doi: 10.1136/jitc-2022-004653. Full text in Research Archive Show summary

  Background Colorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast cells (MCs) promote or inhibit the development of CRC. Herein we investigated MC activity throughout the multistepped development of CRC in both human patients and animal models. Methods We analyzed human patient matched samples of healthy colon vs CRC tissue alongside conducting a The Cancer Genome Atlas-based immunogenomic analysis and multiple experiments employing genetically engineered mouse (GEM) models. Results Analyzing human CRC samples revealed that MCs can be active or inactive in this disease. An activated MC population decreased the number of tumor-residing CD8 T cells. In mice, MC deficiency decreased the development of CA-CRC lesions, while it increased the density of tumor-based CD8 infiltration. Furthermore, co-culture experiments revealed that tumor-primed MCs promote apoptosis in CRC cells. In MC-deficient mice, we found that MCs inhibited the development of sCRC lesions. Further exploration of this with several GEM models confirmed that different immune responses alter and are altered by MC activity, which directly alters colon tumorigenesis. Since rescuing MC activity with bone marrow transplantation in MC-deficient mice or pharmacologically inhibiting MC effects impacts the development of sCRC lesions, we explored its therapeutic potential against CRC. MC activity promoted CRC cell engraftment by inhibiting CD8+ cell infiltration in tumors, pharmacologically blocking it inhibits the ability of allograft tumors to develop. This therapeutic strategy potentiated the cytotoxic activity of fluorouracil chemotherapy. Conclusion Therefore, we suggest that MCs have a dual role throughout CRC development and are potential druggable targets against this disease.

• Saaed, Usman; Myklebust, Tor Åge; Robsahm, Trude Eid; Kielland, Marlene Fritsch; Møller, Bjørn & Skålhegg, Bjørn Steen [Show all 8 contributors for this article] (2022). Risk and survival in colorectal cancer with increasing body mass index: A nationwide population-based cohort study. Colorectal Disease. ISSN 1462-8910. p. 1–11. doi: 10.1111/codi.16367. Full text in Research Archive Show summary

  Aim: The aim was to explore potential associations between the body mass index (BMI) and the risk of colorectal cancer (CRC), including subsites of the colon, and cancer-specific death. Methods: A registry-based cohort study was conducted with baseline data gathered from the Norwegian Tuberculosis Screening Programme, collected between 1963 and 1975, and linked to follow-up data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. Cox regression models were used to explore associations between BMI and CRC risk and cancer-specific death. Results: Of 1 723 692 included individuals, 76 616 developed CRC during 55 370 707 person-years of follow-up. In men, a 5 kg/m2 increase in BMI was associated with an increased risk of colon cancer, including both right and left subsites, and rectal cancer. Allowing for nonlinearities, we found a U-shaped association for the right colon and an inverse U-shape for the left colon and rectum cancer. In women, a 5 kg/m2 increase in BMI in early adulthood was associated with increased risk of colon cancer, including both subsites. In women, an increased risk of CRC death with increasing BMI was found for colon cancer. Conclusions: Men of all ages have an increased risk of CRC with increasing BMI, with the highest risk for right-sided colon cancer. An increased risk for colon cancer was also found in women with high BMI in early adulthood. Furthermore, women of all age groups appeared to have an increased risk of CRC death with higher BMI.

• Kolan, Shrikant; Li, Gaoyang; Grimolizzi, Franco; Sexton, Joseph; Kvien, Tore Kristian & Goll, Guro Løvik [Show all 11 contributors for this article] (2022). Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis. Frontiers in Pharmacology. 13. doi: 10.3389/fphar.2022.1075603. Full text in Research Archive Show summary

  Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12–24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.

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• Granly, Emma Nilsen; Åhrling, Samaneh Shabani; Alvik, Karoline; Das, Siddhartha & Matthews, Jason (2025). Aryl Hydrocarbon Receptor Differentially Regulated Gene Expression Profiles in Resting and Polarized Bone Marrow-Derived Macrophages. Full text in Research Archive
• Åhrling, Samaneh Shabani; Das, Siddhartha; Olafsen, Ninni Elise; Granly, Emma Nilsen & Matthews, Jason (2025). Differential Effects of Loss and Pharmacological Inhibition of Aryl Hydrocarbon Receptor on Mammary Tumor Growth. Full text in Research Archive
• Skålhegg, Bjørn Steen (2025). Endokrine og nevrale sult- og metthetsmekanismer. Hvordan endres de med alderen, og hvilken rolle spiller de ved underernæring? Full text in Research Archive
• Skålhegg, Bjørn Steen (2025). Can profiles of plasma amino acids and derivatives in patients with PDAC be used to predict overall survival? Full text in Research Archive
• Andersen, Lene Frost; Lillegaard, Inger Therese Laugsand; Mangschou, Bente; Medin, Anine Christine; Aakre, Inger & Dalen, Knut Tomas [Show all 12 contributors for this article] (2025). New update of a fortification model. VKM Bulletin. VKM Bulletin 2025: 13(Bulletin 2025: 13), p. 1–34. Full text in Research Archive Show summary

  VKM has calculated the intakes of vitamins and minerals and compared them with the tolerable upper intake levels (UL) in a model for assessing the fortification of food and drink. Fortification means adding vitamins and minerals. The intake calculations cover all age groups. The model has been updated with data from a new dietary survey for adults, and with new tolerable upper intake levels from EFSA for several of the vitamins and minerals. Some of the data entered into the model has been taken from Danish dietary surveys, as there is no Norwegian data available. For most nutrients, it is the amount that can be added for 1- and 2-year-olds that regulates the fortification. The model was established in 2006, and has been updated in 2009, 2013 and 2021. The model does not include the risk of low intake of nutrients. The work has been commissioned by the Norwegian Food Safety Authority, which will use the results from the model as part of the basis for assessing applications for food fortification.

• Wik, Jonas Aakre; Strømsnes, Kristine Bakklund & Skålhegg, Bjørn Steen (2025). Using Seahorse technology as an efficient way of verifying T-cell stimulation. Methods in molecular biology. ISSN 1064-3745. doi: 10.1007/978-1-0716-4414-0_16. Full text in Research Archive
• Schultz, Gry Irene Granli; Parr, Christine Louise; Trosvik, Pål; Yazdankhah, Siamak Pour; Andersen, Lene Frost & Dalen, Knut Tomas [Show all 14 contributors for this article] (2025). Health risk assessment of Bifidobacterium breve M-16V in infant formula. VKM Bulletin. 2025(VKM Bulletin 2025: 09), p. 1–115. Full text in Research Archive Show summary

  VKM has not identified any short-term negative health effects from consuming infant formula with Bifidobacterium breve M-16V. However, there is uncertainty and limited research on possible long-term effects. There is also little research conducted independently of the manufacturers. The Norwegian Food Safety Authority has asked VKM to assess whether there may be health risks associated with giving infants (up to 12 months) infant formula supplemented with a specific probiotic bacterium (Bifidobacterium breve M-16V). "Probiotics" generally refers to health products containing live microorganisms, usually bacteria. Currently, some infant formulas outside Norway are supplemented with freeze-dried probiotic bacteria. The bacterium Bifidobacterium breve M-16V (B. breve M-16V) in given concentrations is considered safe in the USA and EU for use in food, but this status is regularly reviewed in the EU and may change if negative health effects are discovered. In infants, the intestinal microbiota (composition of microorganisms) and immune system are not fully developed, and it is uncertain whether the addition of high doses of probiotic bacteria during infancy may have unintended long-term effects. Background for the risk assessment A company has applied to the Norwegian Food Safety Authority to market two specific infant formulas in Norway: one peptide-based and another amino acid-based. The products are intended for infants having allergies and are regulated as foods for special medical purposes. Both products are supplemented with the probiotic bacterium B. breve M-16V. The Norwegian Food Safety Authority has asked VKM to assess whether there may be health risks associated with giving infants these products specifically, and infant formula supplemented with B. breve M-16V in general. VKM’s methodology A multidisciplinary project group appointed by VKM has reviewed documentation from the company. The group has also conducted a systematic literature review of health effects reported in studies where infants received infant formula supplemented with B. breve M-16V and calculated the possible intake of infant formula and B. breve M-16V among Norwegian infants. VKM has only assessed the risk of negative health effects based on the assignment and according to guidelines for probiotics in food, not as a medicinal product. The assessment has been approved by a multidisciplinary approval group, also appointed by VKM. Findings VKM has not found any unwanted properties of B. breve M-16V based on reported laboratory studies and animal experiments. VKM has also not found negative health effects in 13 clinical studies involving a total of 1580 children, of whom 836 received infant formula supplemented with B. breve M-16V (test) and the rest received infant formula without B. breve M-16V (control). The studies lasted from 6 weeks to 12 months (median 16 weeks). VKM found no consistent differences between test and control groups in reported side effects, children's growth, or symptoms from the gastrointestinal tract, skin, or respiratory system as long as the studies were ongoing (short-term). VKM has found only two studies of long-term effects in children one year (development of asthma symptoms) or 3-5 years (neurocognitive outcomes) after they received infant formula with B. breve M-16V. This is too little to draw conclusions about long-term effects.

• Vinicius, Kannen Cardoso,; Olafsen, Ninni Elise; Paola, Cappello,; Toivo, Maimets,; Indrek, Teino, & Kristaps, Jaudzems, [Show all 10 contributors for this article] (2024). Loss of AHR in CR705 pancreatic cancer cells reduces tumor development due to increased anti-tumor immune responses. Full text in Research Archive Show summary

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly forms of cancer due to late diagnosis and lack of treatment options. One promising therapeutic strategy is to increase immune cell infiltration to the tumor microenvironment. The aryl hydrocarbon receptor (AHR) is an essential gatekeeper integrating metabolic signals to promote immunosuppression, regulate effector immune cells and enhance tumorigenesis. AHR’s immunosuppressive actions allow tumor cells to “hide” from immunosurveillance. To investigate whether loss of AHR protects against PDAC, we used the murine pancreatic cancer cell line, CR705, and generated CR705 AhrKO cells using CRISPR/Cas9. Loss of AHR did not affect cell proliferation compared with WT. Consistent with these findings, WT and AhrKO CR705 cells were injected subcutaneous in immune incompetent NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice or immune competent C57BL/6J mice. We did not observe any differences in tumor development between injection of WT cells compared with AhrKO CR705 cells into NSG mice. However, when these cell lines were injection into C57BL/6J mice, tumors from CR705 AhrKO cells developed significantly slower than tumors from CR705 WT cells. Histological analyses revealed an increased immune cell infiltration, including CD3+ and CD8+ T-cells, and macrophages. RNA sequencing of the tumors resulted in 1091 genes upregulated and 576 genes downregulated in AhrKO tumors compared with WT tumors. Pathway analysis revealed that T cell activation, adaptive immune response and lymphocyte mediated immunity were among the top 5 upregulated pathways. Collectively, these results of this study support the idea of targeting AHR as a therapeutic strategy against PDAC.

• Steffensen, Inger-Lise Karin; Bodin, Johanna Eva; Dalen, Knut Tomas; Mangschou, Bente; Aakre, Inger & Andersen, Lene Frost [Show all 13 contributors for this article] (2024). Risk assessment of quercetin dihydrate and rutin in food supplements – “Other substances”. VKM Bulletin. 2024(9), p. 1–149. Full text in Research Archive Show summary

  Det er trygt å bruke flavonoidene quercetin eller rutin i bestemte i kosttilskudd, ifølge Vitenskapskomiteen for mat og miljø (VKM). Det er hovedbudskapet i en risikovurdering utført på oppdrag fra Mattilsynet. I rapporten ble det konkludert at det er trygt å bruke quercetin eller rutin i kosttilskudd i daglige doser på 5 mg rutin for barn fra fireårsalderen, daglige doser på 25 mg rutin for voksne og 500 mg quercetin dihydrat for voksne i hvert fall opp til tre måneder. VKM har vurdert risiko for helseskadelige effekter ved daglig inntak av kosttilskudd med 25 mg rutin eller 500 mg quercetin dihydrat for voksne fra 18 år og eldre, og 5 mg rutin for barn fra fireårsalderen. Quercetin og rutin er flavonoider. Disse finnes naturlig i planter og inngår i kosten, særlig i frukt, grønnsaker og te. Mange flavonoider fra mat og drikke tas i liten grad opp i kroppen. Risikovurderingen er basert på informasjon fra en systematisk kunnskapsoppsummering av 23 randomiserte kontrollerte studier (studier hvor man undersøker effekten av en behandling ved å fordele deltagere tilfeldig i behandlings- og kontrollgruppe(r). Disse studiene omfattet voksne mennesker. I tillegg er det brukt kunnskap om hvordan stoffene håndteres i kroppen og noen dyrestudier i vurderingen. Studiene hadde undersøkt, men funnet få, og lite alvorlige, skadelige helseeffekter. Den lengste studien varte i 10 måneder. Konklusjonen for barna er basert på studiene av voksne og én studie spesifikk av barn. På grunn av mangel på tilstrekkelige data om gravide kvinner og fostre, og mangel på data om ammende kvinner og deres spedbarn, samt om barn generelt, er det ikke kjent om disse gruppene potensielt kan være mer sårbare for disse stoffene enn voksne. Studiene i mennesker undersøkte hovedsakelig positive effekter av quercetin og rutin for en rekke ulike tilstander og sykdommer. Mulige helseskadelige effekter ble dokumentert og undersøkt i varierende grad, og svært få og lite alvorlige skadelige effekter ble observert. Resultatene understøttes også av dyrestudiene. Ettersom de fleste studiene med quercetin og rutin ikke undersøkte bruk av stoffene i mer enn tre måneder, er lengre tids inntak mer usikkert, selv om noen få studier heller ikke fant skadelige effekter etter bruk i seks til ti måneder, sier Inger-Lise Steffensen, faglig leder av arbeidet. VKM har ikke beregnet bidrag fra andre kilder til rutin eller quercetin som mat, og har heller ikke vurdert bruk av stoffene til behandling av ulike tilstander og sykdommer. Noe data kan tyde på at personer med kronisk nyresykdom eller østrogen-avhengig kreft kanskje kan være sårbare for skadelige effekter av quercetin. Studier i mennesker og dyr har vist at quercetin kan påvirke opptaket av ulike medikamenter i kroppen, og kan påvirke enzymer som omdanner medikamenter. Om quercetin og rutin Quercetin og rutin inngår i gruppen “andre stoffer”. Dette er stoffer med ernæringsmessig eller fysiologisk effekt, og som ikke er vitaminer eller mineraler. Risikovurderingen er godkjent av VKMs faggruppe for ernæring, dietetiske produkter, ny mat og allergi.

• Skålhegg, Bjørn Steen (2024). Nutrition and Pancreatic Cancer.. Food Matters. Full text in Research Archive
• Clauss, Matthieu; Burkhardt, Meike; Wöber, Sophie; Skålhegg, Bjørn Steen & Jensen, Jørgen (2024). Corrigendum: Effect of five hours of mixed exercise on urinary nitrogen excretion in healthy moderate-to-well-trained young adults, (Front. Nutr, (2024), 11, (1345922), 10.3389/fnut.2024.1345922). Frontiers in Nutrition. 11. doi: 10.3389/fnut.2024.1406641. Full text in Research Archive
• Rundblad, Amanda; Hansen, Anna Lena; Christensen, Jacob Juel; Melnes, Torunn; Ottestad, Inger Olaug & Narverud, Ingunn [Show all 12 contributors for this article] (2023). Patients with familial hypercholesterolemia have shorter telomeres than controls in older, but not in young subjects: a cross-sectional study. Full text in Research Archive
• Stålberg, Stina Margrethe; Silwat-Pandit, Laxmi; Hamfjord, Julian; Nebdal, Daniel JH; Lehtiö, Janne & Skålhegg, Bjørn Steen [Show all 7 contributors for this article] (2023). Elevated protein expression levels of KRAS in Pancreatic Ductal Adenocarcinoma (PDAC) are associated with better prognosis. Full text in Research Archive
• Rundblad, Amanda; Das, Siddhartha; Matthews, Jason; Ginos, Gina; Kavousi, Maryam & Holven, Kirsten Bjørklund [Show all 7 contributors for this article] (2023). Air pollution, built environment and associations with gene expression and CVD risk markers in adults. Full text in Research Archive
• Guo, Shuai; Kolan, Shrikant Shantilal; Li, Gaoyang; Hammarstrøm, Clara L; Aure, Miriam Ragle & Stuhr, Linda Elin Birkhaug [Show all 8 contributors for this article] (2023). Ablation of PKA-Cβ2 subunit in mice curtails progression of breast adenocarcinoma and turns "cold" tumor "hot". Full text in Research Archive
• Pedersen, Mona Elisabeth; Rønning, Sissel Beate & Kolset, Svein Olav (2023). Editorial: Growth and Tissue Regeneration with focus on Proteoglycans. Frontiers in Cell and Developmental Biology. 11, p. 1–2. doi: 10.3389/fcell.2023.1139044. Full text in Research Archive
• Five, May-Britt & Rasmussen, Marit (2023). Oppskriften på deg. Full text in Research Archive
• Rasmussen, Marit (2023). Oppskriften på deg. Full text in Research Archive
• Pejšková, Lucie; Rønning, Sissel Beate; Kent, Matthew Peter; Wold, Jens Petter; Mosleth, Ellen Færgestad & Høst, Vibeke [Show all 11 contributors for this article] (2023). Shedding of syndecans play a crucial role in the extensive remodelling of the extracellular matrix in skeletal muscle myopathy in chicken. Full text in Research Archive
• Pejšková, Lucie; Rønning, Sissel Beate; Kent, Matthew Peter; Høst, Vibeke; Solberg, Nina & Kolset, Svein Olav [Show all 9 contributors for this article] (2023). Syndecans as potential regulators of the severe skeletal muscle myopathy. Full text in Research Archive
• Zegeye, Fikirte Debebe; Samulin-Erdem, Johanna Maria; Straumfors, Anne & Matthews, Jason (2026). Occupational exposure and associated health effects among workers in the shrimp processing industry. Universitetet i Oslo. ISSN 9788234807909. Full text in Research Archive Show summary

  Respiratory ailments, such as cough, breathlessness, asthma and allergy, are prevalent among workers in the seafood industry. These health problems have largely been attributed to exposure to allergenic proteins, yet the contributions of other components in the work environment remain insufficiently understood. The aim of this thesis was to investigate the relationship between occupational exposure to allergenic proteins and microbial agents in shrimp processing environments and respiratory health outcomes, including symptoms, allergic sensitisation, and inflammatory responses. Respiratory symptoms as well as allergy and asthma-related biomarkers were assessed among Norwegian shrimp processing workers using questionnaires and blood analyses. Occupational exposure was characterised through work-environment air sampling, protein measurements, microbial identification, and proteomic analyses. Shrimp processing workers reported a higher prevalence of upper and chronic lower respiratory symptoms than controls and exhibited elevated levels of inflammatory, allergy and asthma-related biomarkers. Multiple known and potential shrimp allergens were identified in workplace air, with particularly high levels of tropomyosin detected during shrimp cooking. Airborne microbial exposure was further characterised across different shrimp processing tasks using full-shift personal air sampling and molecular analyses. Higher bacterial load, species richness, and immune activation potential were observed during work processes involving raw shrimp, while cooking substantially reduced bacterial exposure. Experimental studies using human alveolar co-culture cell models demonstrated that combined exposure to shrimp allergens and microbial components can enhance inflammatory responses relative to individual exposures. Overall, the findings demonstrate that complex occupational bioaerosol exposure contributes to respiratory health risks among shrimp-processing workers, with task-specific exposure differences underscoring the need for targeted preventive measures.

• Mikkelsen, Johanne Kristofina; Dalen, Knut Tomas & Hjorth, Marit (2025). Investigating the Role of Perilipin 2 in Atherosclerosis. Universitetet i Oslo. Full text in Research Archive Show summary

  Introduction: Cardiovascular disease (CVD) remains the leading cause of death globally, with atherosclerosis as its primary driver. Atherosclerosis is a chronic inflammatory disease characterised by lipoprotein retention in the arterial wall, macrophage infiltration, and lesion formation. Lipid droplets (LDs) in foam cells store neutral lipids such as triacylglycerol (TAG) and cholesteryl esters (CEs), regulated by LD-associated proteins, including the perilipin (Plin) family. Although Plin2 is highly expressed in macrophages, its role in atherosclerosis is unclear. Materials and methods: To investigate the role of Plin2 in atherosclerosis, male Plin2+/+ and Plin2-/- C57BL/6N mice were injected at 13 weeks of age with an adeno-associated virus serotype 8 (AAV8) carrying a D377Y-mutant murine pro-protein convertase subtilisin/kexin type 9 (Pcsk9) or left uninjected. All mice were subsequently fed an atherogenic diet high in fat, cholesterol, and sucrose. Validation of the AAV model was performed by RT-qPCR, immunoblotting, and measurements of circulating levels of TAG and cholesterol. Body composition, body and organ weights, and hepatic lipid levels were measured. Atherosclerotic lesions in the aortic arch were quantified by lipid staining and image analysis. Bone marrow-derived macrophages (BMDMs) were treated in vitro with cholesterol and oleic acid (OA) and analysed for LD accumulation and gene expression. Results: The AAV8-mPcsk9-D377Y model successfully induced hyperlipidaemia, marked by elevated levels of plasma TAG and cholesterol, due to increased hepatic Pcsk9 mRNA expression and reduced Ldlr protein expression. Plin2 deletion did not affect atherosclerotic lesion size but was associated with reduced body weight and fat mass, and reduced lipid accumulation in liver and plasma. Plin2-deficient BMDMs appeared to accumulate fewer LDs, without any major effects on the expression of genes related to lipid metabolism, inflammation, or immune responses. Conclusion: The findings in this study confirm and highlight a role for Plin2 in systemic and hepatic lipid regulation. Although Plin2 deletion did not reduce atherosclerotic lesions under the tested conditions, its effects on lipid accumulation in liver, plasma, and macrophages warrant further research to investigate its role as a potential therapeutic target in atherosclerosis.

• Andreassen, R. Christel; Kolset, Svein Olav; Rønning, Sissel Beate & Pedersen, Mona Elisabeth (2022). Sustainable bioproduction of animal proteins for human consumption and optimizing the use of protein rich by-products from the food industry. Universitetet i Oslo. Full text in Research Archive Show summary

  The global population growth is posing enormous challenges to the sustainability of the current food pro-duction system. The average consumption of meat has tripled over the last 50 years, and meat consump-tion tends to rise as people get richer, threatening to make high-quality meat and animal protein products a limited resource. Conventional meat production is associated with considerable negative environmental impacts. Sustainable development approaches include achieving responsible production, use, and con-sumption of meat products. Along with meat production, significant quantities of organic waste by-products related to environmental pollution are generated. These by-products contain high-quality pro-teins and nutrients that are currently underused. Opportunities to extract additional value from by-products and sustainable alternatives to conventional meat production should be examined. A promising alternative to the traditional way of producing animal proteins is cultured meat. This meat bypasses animal production by growing muscle cells under a suitable cell culture medium in bioreactors and can potentially be produced more sustainably and efficiently than conventional meat. Despite a high uncertainty due to the early developmental stage of the technology, life-cycle analyses suggest that cultured meat production requires 90% less land, 75% less water, 95% less eutrophication while contributing to 75% less greenhouse gas emissions. At the same time, cultured meat could provide an opportunity for more responsible waste by-product management. However, there are major technological hurdles to overcome until cultured meat can be served at the dinner table, such as formulating a cost-effective serum-free media (SFM), de-veloping suitable scaffolds necessary for muscle cell attachment, and optimizing large-scale production. By-products are low-cost, easy to obtain, food-safe ingredients with potential cell-stimulating and biocom-patible properties. Therefore, they have excellent potential as ingredients in a tailor-made SFM and as muscle cell scaffolding support. In this project, the aim was to solve challenges in cultured meat technology by investigating the feasibility of implementing by-products in the production process. Bovine skeletal muscle satellite cells (MuSCs) were isolated from Longissimus thoracis (beef sirloin). A scaffold-based de-sign was used with microcarriers (MCs) providing permanent support to bovine skeletal muscle satellite cell (MuSC) monocultures in different sized bioreactors. Protein hydrolysates and edible MCs were produced from by-products, characterized, and evaluated for their cell growth-promoting efficiency. Further, long-term and scalable cell expansion parameters were investigated from low volume spinner flasks to higher volume bench-bioreactors. The properties studied confirmed that various by-product hydrolysates and fractions effectively maintained cell growth in SFM. Further, the MCs produced using collagen extracted from turkey tendons, and powdered eggshell membrane (ESM) provided high cell culture expansion effi-ciency. After more than a month, MuSCs expanded in bench-bioreactors retained their proliferative and migratory capacity after dissociation from MCs, indicating that the stem cell pool was well maintained. These are functional cell qualities essential for achieving the massive quantities of MuSCs required in cul-tured meat production. Also, low volume spinner flask cultures with less controlled environments were robustly reproducible in bench-bioreactors. Therefore, low volume spinner flasks can be used as higher throughput and scaled-down models to optimize MuSCs expansion on MCs. This work provides a promis-ing start for developing a sustainable SFM for cultured meat production while reducing the problematic reliance on culture media cost drivers such as serum and commercial growth factors. More importantly, it contributes to a more responsible waste by-product management, representing a significantly more effec-tive protein conversion strategy while contributing to a circular economy by reducing waste. Furthermore, it was demonstrated that by-products with minimal processing successfully functions as MCs for bovine MuSCs in spinner flask culture. Finally, this work provides much-needed publicly accessible data on MuSCs growth kinetics, behavior, and development, especially in high volume bioreactors, and is a promising start to optimize cell expansion parameters adapted to muscle cells.

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