marithjo

• 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
• 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.

• 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.

• Nolsøe, Jens Mortansson Jelstrup; Underhaug, Jarl; Sørskår, Åshild Moi; Antonsen, Simen; Malterud, Karl Egil & Gani, Osman [Show all 11 contributors for this article] (2024). Biological Evaluations, NMR Analyses, Molecular Modeling Studies, and Overview of the Synthesis of the Marine Natural Product (−)-Mucosin. Molecules. ISSN 1431-5157. 29(5). doi: 10.3390/molecules29050994. Full text in Research Archive Show summary

  Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (−)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (−)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (−)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (−)-mucosin (1) is also presented.

• 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.

• 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.

• 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.

• Hjorth, Marit; Galigniana, Natalia; Ween, Ola; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Dalen, Knut Tomas [Show all 7 contributors for this article] (2022). Postprandial Effects of Salmon Fishmeal and Whey on Metabolic Markers in Serum and Gene Expression in Liver Cells. Nutrients. 14(8). doi: 10.3390/nu14081593. Full text in Research Archive Show summary

  Fish is considered an important part of a healthy diet, in part due to the content of long chain omega-3 fatty acids. However, both lean and fatty fish have beneficial health effects, suggesting that micronutrients and proteins may play a role. In a randomised, controlled, cross-over trial, five healthy male participants consumed 5.2 g of protein from either salmon fishmeal or whey. Blood samples were taken before and 30 and 60 min after intake. The concentration of glucose, lipids, hormones and metabolites, including 28 different amino acids and derivatives, were measured in serum or plasma. Cultured HepG2 cells were incubated with or without serum from the participants, and transcriptomic profiling was performed using RNA sequencing. The ingestion of both salmon fishmeal and whey reduced the glucose and triglyceride levels in serum. Protein intake, independent of the source, increased the concentration of 22 amino acids and derivatives in serum. Fishmeal increased the concentration of arginine, methionine, serine, glycine, cystathionine and 2-aminobutyric acid more than whey did. Incubation with postprandial serum resulted in large transcriptomic alterations in serum-fasted HepG2 cells, with the differential expression of >4500 protein coding genes. However, when comparing cells cultivated in fasting serum to postprandial serum after the ingestion of fishmeal and whey, we did not detect any differentially regulated genes, neither with respect to the protein source nor with respect to the time after the meal. The comparable nutrigenomic effects of fishmeal and whey do not change the relevance of fish by-products as an alternative food source.

• Torp, May-Kristin; Ranheim, Trine; Schjalm, Camilla; Hjorth, Marit; Heiestad, Christina Mathisen & Dalen, Knut Tomas [Show all 13 contributors for this article] (2022). Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis. Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.870811. Full text in Research Archive Show summary

  The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.

• Hjorth, Marit; Doncheva, Atanaska Ivanova; Norheim, Frode Amador; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Sæther, Thomas [Show all 7 contributors for this article] (2022). Consumption of salmon fishmeal increases hepatic cholesterol content in obese C57BL/6 J mice. European Journal of Nutrition. ISSN 1436-6207. 61, p. 4027–4043. doi: 10.1007/s00394-022-02930-y. Full text in Research Archive Show summary

  Abstract Purpose By-products from farmed fish contain large amounts of proteins and may be used for human consumption. The purpose of this study was to investigate cardiometabolic effects and metabolic tolerance in mice consuming fishmeal from salmon by-products, salmon filet or beef. Methods Female C57BL/6J mice were fed chow, as a healthy reference group, or a high-fat diet for 10 weeks to induce obesity and glucose intolerance. Obese mice were subsequently given isocaloric diets containing 50% of the dietary protein from salmon fishmeal, salmon filet or beef for 10 weeks. Mice were subjected to metabolic phenotyping, which included measurements of body composition, energy metabolism in metabolic cages and glucose tolerance. Lipid content and markers of hepatic toxicity were determined in plasma and liver. Hepatic gene and protein expression was determined with RNA sequencing and immunoblotting. Results Mice fed fishmeal, salmon filet or beef had similar food intake, energy consumption, body weight gain, adiposity, glucose tolerance and circulating levels of lipids and hepatic toxicity markers, such as p-ALT and p-AST. Fishmeal increased hepatic cholesterol levels by 35–36% as compared to salmon filet (p = 0.0001) and beef (p = 0.005). This was accompanied by repressed expression of genes involved in steroid and cholesterol metabolism and reduced levels of circulating Pcsk9. Conclusion Salmon fishmeal was well tolerated, but increased hepatic cholesterol content. The high cholesterol content in fishmeal may be responsible for the effects on hepatic cholesterol metabolism. Before introducing fishmeal from salmon by-products as a dietary component, it may be advantageous to reduce the cholesterol content in fishmeal. Introduction

• Doncheva, Atanaska Ivanova; Norheim, Frode Amador; Hjorth, Marit; Grujic, Mirjana; Paivandy, Aida & Dankel, Simon N [Show all 14 contributors for this article] (2021). Serglycin Is Involved in Adipose Tissue Inflammation in Obesity. Journal of Immunology. ISSN 0022-1767. 208(1), p. 121–132. doi: 10.4049/jimmunol.2100231. Full text in Research Archive Show summary

  Chronic local inflammation of adipose tissue is an important feature of obesity. Serglycin is a proteoglycan highly expressed by various immune cell types known to infiltrate adipose tissue under obese conditions. To investigate if serglycin expression has an impact on diet-induced adipose tissue inflammation, we subjected Srgn+/+ and Srgn−/− mice (C57BL/6J genetic background) to an 8-wk high-fat and high-sucrose diet. The total body weight was the same in Srgn+/+ and Srgn−/− mice after diet treatment. Expression of white adipose tissue genes linked to inflammatory pathways were lower in Srgn−/− mice. We also noted reduced total macrophage abundance, a reduced proportion of proinflammatory M1 macrophages, and reduced formation of crown-like structures in adipose tissue of Srgn−/− compared with Srgn+/+ mice. Further, Srgn−/− mice had more medium-sized adipocytes and fewer large adipocytes. Differentiation of preadipocytes into adipocytes (3T3-L1) was accompanied by reduced Srgn mRNA expression. In line with this, analysis of single-cell RNA sequencing data from mouse and human adipose tissue supports that Srgn mRNA is predominantly expressed by various immune cells, with low expression in adipocytes. Srgn mRNA expression was higher in obese compared with lean humans and mice, accompanied by an increased expression of immune cell gene markers. SRGN and inflammatory marker mRNA expression was reduced upon substantial weight loss in patients after bariatric surgery. Taken together, this study introduces a role for serglycin in the regulation of obesity-induced adipose inflammation.

• Li, Yuchuan; Khanal, Prabhat; Norheim, Frode; Hjorth, Marit; Bjellaas, Thomas & Drevon, Christian A [Show all 9 contributors for this article] (2021). Plin2 deletion increases cholesteryl ester lipid droplet content and disturbs cholesterol balance in adrenal cortex. Journal of Lipid Research. ISSN 0022-2275. 62. doi: 10.1016/J.JLR.2021.100048. Full text in Research Archive Show summary

  Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. Steroidogenic cells primarily store CEs in cytoplasmic lipid droplet (LD) organelles, as contrasted to the majority of mammalian cell types that predominantly store triacylglycerol (TAG) in LDs. The LD-binding Plin2 binds to both CE- and TAG-rich LDs, and although Plin2 is known to regulate degradation of TAG-rich LDs, its role for regulation of CE-rich LDs is unclear. To investigate the role of Plin2 in the regulation of CE-rich LDs, we performed histological and molecular characterization of adrenal glands from Plin2+/+ and Plin2−/− mice. Adrenal glands of Plin2−/− mice had significantly enlarged organ size, increased size and numbers of CE-rich LDs in cortical cells, elevated cellular unesterified cholesterol levels, and increased expression of macrophage markers and genes facilitating reverse cholesterol transport. Despite altered LD storage, mobilization of adrenal LDs and secretion of corticosterone induced by adrenocorticotropic hormone stimulation or starvation were similar in Plin2+/+ and Plin2−/− mice. Plin2−/− adrenals accumulated ceroid-like structures rich in multilamellar bodies in the adrenal cortex-medulla boundary, which increased with age, particularly in females. Finally, Plin2−/− mice displayed unexpectedly high levels of phosphatidylglycerols, which directly paralleled the accumulation of these ceroid-like structures. Our findings demonstrate an important role of Plin2 for regulation of CE-rich LDs and cellular cholesterol balance in the adrenal cortex.

• Hustad, Kristin Solheim; Ottestad, Inger Olaug; Hjorth, Marit; Dalen, Knut Tomas; Sæther, Thomas & Sheikh, Navida Akhter [Show all 9 contributors for this article] (2021). No effect of salmon fish protein on 2-h glucose in adults with increased risk of type 2 diabetes: a randomised controlled trial. British Journal of Nutrition. ISSN 0007-1145. 126(9), p. 1304–1313. doi: 10.1017/S0007114521000040. Full text in Research Archive Show summary

  Abstract The association between fish consumption and decreased risk of CVD is well documented. However, studies on health effects of fish consumption suggest that other components than n -3 PUFA have beneficial cardiometabolic effects, including effects on glucose metabolism. The aim of the present study was to investigate effects of salmon fish protein on cardiometabolic risk markers in a double-blind, randomised controlled parallel trial. We hypothesised that daily intake of a salmon fish protein supplement for 8 weeks would improve glucose tolerance in persons with increased risk of type 2 diabetes mellitus (T2DM). Our primary outcome measure was serum glucose (s-glucose) 2 h after a standardised oral glucose tolerance test. In total, eighty-eight adults with elevated s-glucose levels were randomised to 7·5 g of salmon fish protein/d or placebo, and seventy-four participants were included in the analysis. We found no significant effect of salmon fish protein supplementation on our primary outcome or other markers related to glucose tolerance, serum lipids, weight or blood pressure compared with placebo. The present study does not support the hypothesis that daily intake of a salmon fish protein supplement for 8 weeks improves glucose tolerance in persons with increased risk of T2DM.

• Olsen, Thomas; Øvrebø, Bente; Yasein, Nadia Haj; Lee-Ødegård, Sindre; Svendsen, Karianne & Hjorth, Marit [Show all 11 contributors for this article] (2020). Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study. Journal of Translational Medicine. 18(122). doi: 10.1186/s12967-020-02288-x. Full text in Research Archive Show summary

  Background Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study. Methods Twenty women with overweight or obesity were allocated to a diet low (Met/Cys-low, n = 7), medium (Met/Cys-medium, n = 7) or high (Met/Cys-high, n = 6) in methionine and cysteine for 7 days. The diets differed only by methionine and cysteine content. Blood and urine were collected at day 0, 1, 3 and 7 and subcutaneous adipose tissue biopsies were taken at day 0 and 7. Results Plasma methionine and cystathionine and urinary total cysteine decreased, whereas FGF21 increased in the Met/Cys-low vs. Met/Cys-high group. The Met/Cys-low group had increased mRNA expression of lipogenic genes in adipose tissue including DGAT1. When we excluded one participant with high fasting insulin at baseline, the Met/Cys-low group showed increased expression of ACAC, DGAT1, and tendencies for increased expression of FASN and SCD1 compared to the Met/Cys-high group. The participants reported satisfactory compliance and that the diets were moderately easy to follow. Conclusions Our data suggest that dietary methionine and cysteine restriction may have beneficial effects on circulating biomarkers, including FGF21, and influence subcutaneous adipose tissue gene expression. These results will aid in the design and implementation of future large-scale dietary interventions with methionine and cysteine restriction. Trial registration ClinicalTrials.gov Identifier: NCT03629392, registration date: 14/08/2018 https://clinicaltrials.gov/ct2/show/NCT03629392.

• Whitham, Martin; Pal, Martin; Petzold, Tim; Hjorth, Marit; Egan, Casey L & Brunner, Julia S [Show all 14 contributors for this article] (2019). Adipocyte-specific deletion of IL-6 does not attenuate obesity-induced weight gain or glucose intolerance in mice. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 317(4), p. E597–E604. doi: 10.1152/ajpendo.00206.2019. Full text in Research Archive
• Reibe, Saskia; Hjorth, Marit; Febbraio, Mark A & Whitham, Martin (2018). GeneXX: an online tool for the exploration of transcript changes in skeletal muscle associated with exercise. Physiological Genomics. ISSN 1094-8341. 50(5), p. 376–384. doi: 10.1152/physiolgenomics.00127.2017. Full text in Research Archive
• Hjorth, Marit & Febbraio, Mark A (2018). Exercise as medicine for survivors of paediatric cancer. Nature Reviews Endocrinology. ISSN 1759-5029. 14(9), p. 506–508. doi: 10.1038/s41574-018-0065-6. Full text in Research Archive
• Whitham, Martin; Parker, Benjamin L; Friedrichsen, Martin; Hingst, Janne R; Hjorth, Marit & Hughes, William E [Show all 20 contributors for this article] (2018). Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise. Cell Metabolism. ISSN 1550-4131. 27(1), p. 237–251. doi: 10.1016/j.cmet.2017.12.001. Full text in Research Archive
• Pourteymour, Shirin; Eckardt, Kristin; Holen, Torgeir; Langleite, Torgrim Mikal; Lee, Sindre & Jensen, Jørgen [Show all 9 contributors for this article] (2017). Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines. Molecular Metabolism. 6(4), p. 352–365. doi: 10.1016/j.molmet.2017.01.007. Full text in Research Archive Show summary

  Objective: Skeletal muscle is an important secretory organ, producing and releasing numerous myokines, which may be involved in mediating beneficial health effects of physical activity. More than 100 myokines have been identified by different proteomics approaches, but these techniques may not detect all myokines. We used mRNA sequencing as an untargeted approach to study gene expression of secreted proteins in skeletal muscle upon acute as well as long-term exercise. Methods: Twenty-six middle-aged, sedentary men underwent combined endurance and strength training for 12 weeks. Skeletal muscle biopsies from m. vastus lateralis and blood samples were taken before and after an acute bicycle test, performed at baseline as well as after 12 weeks of training intervention. We identified transcripts encoding secretory proteins that were changed more than 1.5-fold in muscle after exercise. Secretory proteins were defined based on either curated UniProt annotations or predictions made by multiple bioinformatics methods. Results: This approach led to the identification of 161 candidate secretory transcripts that were up-regulated after acute exercise and 99 that where increased after 12 weeks exercise training. Furthermore, 92 secretory transcripts were decreased after acute and/or long-term physical activity. From these responsive transcripts, we selected 17 candidate myokines sensitive to short- and/or long-term exercise that have not been described as myokines before. The expression of these transcripts was confirmed in primary human skeletal muscle cells during in vitro differentiation and electrical pulse stimulation (EPS). One of the candidates we identified was macrophage colony-stimulating factor-1 (CSF1), which influences macrophage homeostasis. CSF1 mRNA increased in skeletal muscle after acute and long-term exercise, which was accompanied by a rise in circulating CSF1 protein. In cultured muscle cells, EPS promoted a significant increase in the expression and secretion of CSF1. Conclusion: We identified 17 new, exercise-responsive transcripts encoding secretory proteins. We further identified CSF1 as a novel myokine, which is secreted from cultured muscle cells and up-regulated in muscle and plasma after acute exercise.

• Hjorth, Marit & Febbraio, Mark A (2017). IL-1β delivers a sweet deal. Nature Immunology. ISSN 1529-2908. 18(3), p. 247–248. doi: 10.1038/ni.3681. Full text in Research Archive
• Pourteymour, Shirin; Hjorth, Marit; Lee-Ødegård, Sindre; Holen, Torgeir; Langleite, Torgrim Mikal & Jensen, Jørgen [Show all 9 contributors for this article] (2017). Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise. Physiological Reports. 5:e13459(19), p. 1–14. doi: 10.14814/phy2.13459. Full text in Research Archive Show summary

  Physical activity promotes specific adaptations in most tissues including skeletal muscle. Acute exercise activates numerous signaling cascades including pathways involving mitogen‐activated protein kinases (MAPKs) such as extracellular signal‐regulated kinase (ERK)1/2, which returns to pre‐exercise level after exercise. The expression of MAPK phosphatases (MKPs) in human skeletal muscle and their regulation by exercise have not been investigated before. In this study, we used mRNA sequencing to monitor regulation of MKPs in human skeletal muscle after acute cycling. In addition, primary human myotubes were used to gain more insights into the regulation of MKPs. The two ERK1/2‐specific MKPs, dual specificity phosphatase 5 (DUSP5) and DUSP6, were the most regulated MKPs in skeletal muscle after acute exercise. DUSP5 expression was ninefold higher immediately after exercise and returned to pre‐exercise level within 2 h, whereas DUSP6 expression was reduced by 43% just after exercise and remained below pre‐exercise level after 2 h recovery. Cultured myotubes express both MKPs, and incubation with dexamethasone (Dex) mimicked the in vivo expression pattern of DUSP5 and DUSP6 caused by exercise. Using a MAPK kinase inhibitor, we showed that stimulation of ERK1/2 activity by Dex was required for induction of DUSP5. However, maintaining basal ERK1/2 activity was required for basal DUSP6 expression suggesting that the effect of Dex on DUSP6 might involve an ERK1/2‐independent mechanism. We conclude that the altered expression of DUSP5 and DUSP6 in skeletal muscle after acute endurance exercise might affect ERK1/2 signaling of importance for adaptations in skeletal muscle during exercise.

• Hjorth, Marit; Pourteymour, Shirin; Goergens, S W; Langleite, Torgrim Mikal; Lee, Sindre & Holen, Torgeir [Show all 11 contributors for this article] (2016). Myostatin in relation to physical activity and dysglycaemia and its effect on energy metabolism in human skeletal muscle cells. Acta Physiologica. ISSN 1748-1708. 217(1), p. 45–60. doi: 10.1111/apha.12631. Full text in Research Archive
• Görgens, Sven W.; Hjorth, Marit; Eckardt, Kristin; Wichert, Stefan; Norheim, Frode & Holen, Torgeir [Show all 16 contributors for this article] (2016). The exercise-regulated myokine chitinase-3-like protein 1 stimulates human myocyte proliferation. Acta Physiologica. ISSN 1748-1708. 216(3), p. 330–345. doi: 10.1111/apha.12579. Full text in Research Archive Show summary

  Aim: Chitinase-3-like protein 1 (CHI3L1) is involved in tissue remodelling and inflammatory processes. Plasma levels are elevated in patients with insulin resistance and T2DM. We recently showed that CHI3L1 and its receptor protease-activated receptor 2 (PAR-2) are expressed in skeletal muscle. Activation of PAR-2 by CHI3L1 protects against TNF- a -induced inflammation and insulin resistance. However, the effect of exercise on CHI3L1 and PAR-2 signalling remains unknown. The aim of this work was to study the impact of exercise on CHI3L1 production and the effect of CHI3L1/PAR-2 signalling on skeletal muscle growth and repair. Methods: Three human exercise studies were used to measure CHI3L1 plasma levels ( n = 32). In addition, muscle and adipose tissue CHI3L1 mRNA expression was measured in response to acute and long-term exer- cise ( n = 24). Primary human skeletal muscle cells were differentiated in vitro, and electrical pulse stimulation was applied. In addition, myo- blasts were incubated with CHI3L1 protein and activation of MAP kinase signalling as well as proliferation was measured. Results: Circulating CHI3L1 levels and muscle CHI3L1 mRNA were increased after acute exercise. In addition, CHI3L1 mRNA expression as well as CHI3L1 secretion was enhanced in electrically stimulated cultured myotubes. Incubation of cultured human myoblasts with CHI3L1 protein leads to a strong activation of p44/42, p38 MAPK and Akt as well as enhanced myoblast proliferation. Conclusion: Our findings suggest that CHI3L1 is induced by acute exer- cise and that CHI3L1/PAR-2 signalling activates myocyte proliferation, which is important for restructuring of skeletal muscle in the response to exercise training.

• Hjorth, Marit; Norheim, Frode; Meen, Astri Jeanette; Pourteymour, Shirin; Lee, Sindre & Holen, Torgeir [Show all 13 contributors for this article] (2015). The effect of acute and long-term physical activity on extracelluar Matrix and serglycin in huuman skeletal muscle. Physiological Reports. 3:e12473(8), p. 1–19. doi: 10.14814/phy2.12473. Full text in Research Archive
• Pourteymour, Shirin; Lee, Sindre; Langleite, Torgrim Mikal; Eckardt, Kristin; Hjorth, Marit & Bindesbøll, Christian [Show all 11 contributors for this article] (2015). Perilipin 4 in human skeletal muscle: localization and effect of physical activity. Physiological Reports. 3:e12481(8), p. 1–15. doi: 10.14814/phy2.12481. Full text in Research Archive
• Norheim, Frode; Langleite, Torgrim Mikal; Hjorth, Marit; Holen, Torgeir; Kielland, Anders & Stadheim, Hans Kristian [Show all 10 contributors for this article] (2014). The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. The FEBS Journal. ISSN 1742-464X. 281(3), p. 739–749. doi: 10.1111/febs.12619. Full text in Research Archive Show summary

  Irisin was first identified as a peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) dependent myokine with the potential to induce murine brown-fat-like development of white adipose tissue. In humans, the regulatory effect of training on muscle FNDC5mRNA expression and subsequently irisin levels in plasma is more controversial. We recruited 26 inactive men (13 normoglycaemic and normal weight, controls; and 13 slightly hyperglycaemic and overweight, pre-diabetes group) aged 40–65 years for a 12-week intervention of combined endurance and strength training with four sessions of training per week. Before and after the 12-week intervention period, participants were exposed to an acute endurance workload of 45 min at 70% of VO2max, and muscle biopsies were taken prior to and after exercise. Skeletal muscle mRNA for PGC1A and FNDC5 correlated and both PGC1A and FNDC5mRNA levels increased after 12 weeks of training in both control and pre-diabetes subjects. Circulating irisin was reduced in response to 12 weeks of training, and was increased acutely (~1.2-fold) just after acute exercise. Plasma concentration of irisin was higher in pre-diabetes subjects compared with controls. There was little effect of 12 weeks of training on selected browning genes in subcutaneous adipose tissue. UCP1mRNA did not correlate with FNDC5 expression in subcutaneous adipose tissue or skeletal muscle or with irisin levels in plasma. We observed no enhancing effect of long-term training on circulating irisin levels, and little or no effect of training on browning of subcutaneous white adipose tissue in humans.

• Norheim, Frode; Hjorth, Marit; Langleite, Torgrim Mikal; Lee, Sindre; Holen, Torgeir & Bindesbøll, Christian [Show all 13 contributors for this article] (2014). Regulation of angiopoietin-like protein 4 Production during and after exercise. Physiological Reports. 2(8), p. 12–12. doi: 10.14814/phy2.12109. Full text in Research Archive
• Norheim, Frode; Gjelstad, Ingrid Merethe Fange; Hjorth, Marit; Vinknes, Kathrine; Langleite, Torgrim Mikal & Holen, Torgeir [Show all 12 contributors for this article] (2012). Molecular nutrition research - the modern way of performing nutritional science. Nutrients. 4(12), p. 1898–1944. doi: 10.3390/nu4121898. Full text in Research Archive Show summary

  In spite of amazing progress in food supply and nutritional science, and a striking increase in life expectancy of approximately 2.5 months per year in many countries during the previous 150 years, modern nutritional research has a great potential of still contributing to improved health for future generations, granted that the revolutions in molecular and systems technologies are applied to nutritional questions. Descriptive and mechanistic studies using state of the art epidemiology, food intake registration, genomics with single nucleotide polymorphisms (SNPs) and epigenomics, transcriptomics, proteomics, metabolomics, advanced biostatistics, imaging, calorimetry, cell biology, challenge tests (meals, exercise, etc.), and integration of all data by systems biology, will provide insight on a much higher level than today in a field we may name molecular nutrition research. To take advantage of all the new technologies scientists should develop international collaboration and gather data in large open access databases like the suggested Nutritional Phenotype database (dbNP). This collaboration will promote standardization of procedures (SOP), and provide a possibility to use collected data in future research projects. The ultimate goals of future nutritional research are to understand the detailed mechanisms of action for how nutrients/foods interact with the body and thereby enhance health and treat diet-related diseases.

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• Hjorth, Marit; Doncheva, Atanaska Ivanova; Norheim, Frode Amador; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Sæther, Thomas [Show all 7 contributors for this article] (2022). Consumption of salmon fishmeal increases hepatic cholesterol content in obese C57BL/6J mice. Full text in Research Archive
• Holven, Kirsten Bjørklund; Sæther, Thomas; Hjorth, Marit; Dalen, Knut Tomas; Ulven, Stine Marie & Ottestad, Inger [Show all 7 contributors for this article] (2019). Kan fisk utnyttes enda mer og samtidig fremme folkehelsen? Norsk tidsskrift for ernæring (NTFE). ISSN 1503-5034. 17(2), p. 20–22. Full text in Research Archive
• Eckardt, Kristin; Pourteymour, Shirin; Hjorth, Marit; Lee, Sindre; Langleite, Torgrim Mikal & Holen, Torgeir [Show all 9 contributors for this article] (2016). Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise. Full text in Research Archive
• 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.

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