Frode Amador Norheim

• 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
• 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
• 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.

• Pourteymour, Shirin; Majhi, Rakesh Kumar; Norheim, Frode Amador & Drevon, Christian André (2025). Exercise Delays Brain Ageing Through Muscle‐Brain Crosstalk. Cell Proliferation. ISSN 0960-7722. 58(7). doi: 10.1111/cpr.70026. Full text in Research Archive Show summary

  Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well‐being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise‐induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle–brain crosstalk. We examine the interaction between the brain with well‐known myokines, including brain‐derived neurotrophic factor, macrophage colony‐stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.

• Suntharalingam, Anita; Sharma, Archana; Qvigstad, Elisabeth; Sattar, Naveed; Gill, Jason M. R. & Bjørnvall, Christina Dybdrodt [Show all 12 contributors for this article] (2025). Differences in tissue-specific insulin resistance between South Asian and Nordic women with prediabetes after gestational diabetes. Diabetologia. ISSN 0012-186X. 68(12), p. 2696–2708. doi: 10.1007/s00125-025-06546-9. Full text in Research Archive Show summary

  Aims/hypothesis The aim of this work was to investigate tissue-specific insulin resistance in South Asian and Nordic women with previous gestational diabetes mellitus (pGDM) and to evaluate potential ethnic differences contributing to type 2 diabetes risk. Methods A cross-sectional study using a two-step hyperinsulinaemic–euglycaemic clamp with a glucose tracer was conducted to assess insulin sensitivity in muscle, liver and adipose tissue in 19 South Asian and 16 Nordic women with pGDM and prediabetes (impaired glucose tolerance and/or impaired fasting glucose), along with 16 ethnicity-specific control women. We assessed inflammation and mitochondrial genes by mRNA sequencing of adipose tissue. Results Both South Asian and Nordic women with pGDM showed reduced total glucose disposal (mainly due to muscle insulin resistance) and hyperinsulinaemia compared with the control group. Endogenous glucose production (mainly due to hepatic insulin resistance) was elevated in Nordics with pGDM, while South Asians with pGDM showed pronounced adipose tissue insulin resistance (reduced suppression of glycerol during clamp). mRNA sequencing of adipose tissue indicated increased tissue inflammation in South Asian women compared with Nordic women with pGDM. Furthermore, we observed a differential response to hyperinsulinaemia in South Asians vs Nordics related to mitochondrial mRNA, such as thymidine kinase 2 (TK2). Correlations between adiposity markers and insulin sensitivity also differed by ethnicity, suggesting that the pathways leading to type 2 diabetes may vary across populations. Conclusions/interpretation South Asian and Nordic women with pGDM exhibited differences in insulin resistance profiles, with South Asians showing greater adipose tissue insulin resistance and inflammation.

• Higa, Ryoko; Pourteymour, Shirin; Kolan, Pratibha Shrikant; Dankel, Simon N; Fernø, Johan & Mellgren, Gunnar [Show all 12 contributors for this article] (2025). Hepatic lipid metabolism is altered in Ubiad1+/- mice of both sexes. Scientific Reports. 15. doi: 10.1038/s41598-025-91283-7. Full text in Research Archive Show summary

  UbiA prenyltransferase domain containing 1 (Ubiad1) has the potential to affect cholesterol and phospholipid levels in different cell types. We previously identified Ubiad1 as a candidate gene for regulating subcutaneous fat pad weight in a mouse genome-wide association study. Here we evaluated the relationship between Ubiad1 and obesity-related traits in cohorts of humans and mice, and in Ubiad1+/− mice fed a high-fat diet. In both humans and mice, adipose tissue Ubiad1 mRNA expression correlated negatively with adiposity and positively with mitochondria-related genes. To determine the role of Ubiad1 in high-fat diet-induced obesity, we disrupted the Ubiad1 gene in mice. Deletion of Ubiad1 was embryonically lethal in C57BL/6 N mice, preventing analysis of adult Ubiad1−/− mice. Thus, male and female Ubiad1+/+ and Ubiad1+/− mice were fed high-fat diet for 10 weeks, with no difference in weight gain and adipose tissue organ weights observed between the genotypes. Analysis of liver mRNA expression revealed that Ubiad1 heterozygosis (Ubiad1+/−) altered several pathways involved in lipid metabolism. Detailed lipid quantification with HPLC-qTOF/MS showed increased levels of hepatic ceramides in female Ubiad1+/− mice, whereas phosphatidylglycerols, phosohatidylinositol and lysophosphatidylethanolamines were reduced in male Ubiad1+/− mice. Our findings reveal sex-specific effects of Ubiad1 expression on hepatic lipid metabolism.

• 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.

• 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.

• 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.

• 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

• Tingstad, Ragna Husby; Norheim, Frode Amador; Haugen, Fred; Feng, Yuan Zeng; Tunsjø, Hege & Thoresen, G. Hege [Show all 9 contributors for this article] (2021). The effect of toll-like receptor ligands on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. Scientific Reports. 11(1). doi: 10.1038/s41598-021-03730-w. Full text in Research Archive Show summary

  Skeletal muscle plays an important role in glycaemic control and metabolic homeostasis, making it a tissue of interest with respect to type 2 diabetes mellitus. The aim of the present study was to determine if ligands of Toll-like receptors (TLRs) could have an impact on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. The myotubes expressed mRNA for TLRs 1–6. TLR3, TLR4, TLR5 and TLR6 ligands (TLRLs) increased glucose metabolism. Furthermore, TLR4L and TLR5L increased oleic acid metabolism. The metabolic effects of TLRLs were not evident until after at least 24 h pre-incubation of the cells and here the metabolic effects were more evident for the metabolism of glucose than oleic acid, with a shift towards effects on oleic acid metabolism after chronic exposure (168 h). However, the stimulatory effect of TLRLs on myokine expression and secretion was detected after only 6 h, where TLR3-6L stimulated secretion of interleukin-6 (IL-6). TLR5L also increased secretion of interleukin-8 (IL-8), while TLR6L also increased secretion of granulocyte–macrophage colony stimulating factor (GM-CSF). Pre-incubation of the myotubes with IL-6 for 24 h increased oleic acid oxidation but had no effect on glucose metabolism. Thus IL-6 did not mimic all the metabolic effects of the TLRLs, implying metabolic effects beyond the actions of this myokine.

• 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.

• Moore, Timothy M.; Terrazas, Anthony; Strumwasser, Alexander R.; Lin, Amanda J.; Zhu, Xiaopeng & Anand, Akshay T. S. [Show all 13 contributors for this article] (2021). Effect of voluntary exercise upon the metabolic syndrome and gut microbiome composition in mice. Physiological Reports. 9(21). doi: 10.14814/phy2.15068. Full text in Research Archive
• Maak, Steffen; Norheim, Frode Amador; Drevon, Christian A & Erickson, Harold P (2021). Progress and Challenges in the Biology of FNDC5 and Irisin. Endocrine reviews. ISSN 0163-769X. 42(4), p. 436–456. doi: 10.1210/endrev/bnab003. Full text in Research Archive Show summary

  Abstract In 2002, a transmembrane protein—now known as FNDC5—was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer’s disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed—mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.

• Norheim, Frode Amador; Krishnan, Karthickeyan Chella; Bjellaas, Thomas; Vergnes, Laurent; Pan, Calvin & Parks, Brian W. [Show all 18 contributors for this article] (2021). Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis. Molecular Systems Biology. 17. doi: 10.15252/msb.20209684. Full text in Research Archive Show summary

  To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

• Aalberg, Karoline; Stavem, Knut; Norheim, Frode Amador; Russell, Michael Bjørn & Chaibi, Aleksander (2021). Effect of oral and transdermal oestrogen therapy on bone mineral density in functional hypothalamic amenorrhoea: A systematic review and meta-analysis. BMJ Open sport & exercise medicine. 7(3). doi: 10.1136/bmjsem-2021-001112. Full text in Research Archive Show summary

  Background Female athletes might develop reduced bone mineral density (BMD) and amenorrhoea due to low energy intake. Objective To systematically review the literature of randomised controlled trials (RCTs) assessing the effect of oestrogen oral contraceptives (OCP), conjugated oestrogens (CE) and transdermal estradiol (TE) on BMD in premenopausal women with functional hypothalamic amenorrhoea (FHA) due to weight loss, vigorous exercise and/or stress. Methods A comprehensive literature search in PubMed, MEDLINE, Cochrane Library, Ovid and CINAHL from inception to 1 October 2020. Data extraction and synthesis Two authors independently extracted data. When possible, the data were pooled in a random-effects meta-analysis. Main outcomes Difference in BMD (g/cm 2 ) at the lumbar spine. Results Nine RCTs comprising 770 participants met the inclusion criteria; five studies applied OCP, two CE and two TE. Four RCTs (two OCP, two TE) found an increased BMD in premenopausal women with FHA, and five (three OCP, two CE) found a decreased BMD compared with controls. A meta-analysis showed no difference in BMD between the treatment and control groups, (standardised mean difference (SMD) 0.30, 95% CI −0.12 to 0.73). A secondary analysis for change scores from baseline to first assessment point, showed a similar overall result (SMD 0.17, 95% CI −0.16 to 0.51). No serious adverse events were reported. Conclusion The literature suggests that TE might increase lumbar BMD in premenopausal women with FHA, but pooled results revealed no effect of the intervention. The findings do not support oestrogen therapy to improve BMD in these patient groups.

• Li, Yuchuan; Torp, May-Kristin; Norheim, Frode; Khanal, Prabhat; Kimmel, Alan R. & Stensløkken, Kåre-Olav [Show all 8 contributors for this article] (2020). Isolated Plin5-deficient cardiomyocytes store less lipid droplets than normal, but without increased sensitivity to hypoxia. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1866(4). doi: 10.1016/j.bbalip.2020.158873. Full text in Research Archive Show summary

  Plin5 is abundantly expressed in the heart where it binds to lipid droplets (LDs) and facilitates physical interaction between LDs and mitochondria. We isolated cardiomyocytes from adult Plin5+/+ and Plin5-/- mice to study the role of Plin5 for fatty acid uptake, LD accumulation, fatty acid oxidation, and tolerance to hypoxia. Cardiomyocytes isolated from Plin5-/- mice cultured with oleic acid stored less LDs than Plin5+/+, but comparable levels to Plin5+/+ cardiomyocytes when adipose triglyceride lipase activity was inhibited. The ability to oxidize fatty acids into CO2 was similar between Plin5+/+ and Plin5-/- cardiomyocytes, but Plin5-/- cardiomyocytes had a transient increase in intracellular fatty acid oxidation intermediates. After pre-incubation with oleic acids, Plin5-/- cardiomyocytes retained a higher content of glycogen and showed improved tolerance to hypoxia compared to Plin5+/+. In isolated, perfused hearts, deletion of Plin5 had no important effect on ventricular pressures or infarct size after ischemia. Old Plin5-/- mice had reduced levels of cardiac triacylglycerides, increased heart weight, and apart from modest elevated expression of mRNAs for beta myosin heavy chain Myh7 and the fatty acid transporter Cd36, other genes involved in fatty acid oxidation, glycogen metabolism and glucose utilization were essentially unchanged by removal of Plin5. Plin5 seems to facilitate cardiac LD storage primarily by repressing adipose triglyceride lipase activity without altering cardiac fatty acid oxidation capacity. Expression of Plin5 and cardiac LD content of isolated cardiomyocytes has little importance for tolerance to acute hypoxia and ischemia, which contrasts the protective role for Plin5 in mouse models during myocardial ischemia.

• 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.

• Zhou, Zhenqi; Moore, Timothy M.; Drew, Brian G.; Ribas, Vicent; Wanagat, Jonathan & Civelek, Mete [Show all 31 contributors for this article] (2020). Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling. Science Translational Medicine. ISSN 1946-6234. 12(555). doi: 10.1126/SCITRANSLMED.AAX8096. Full text in Research Archive Show summary

  Obesity is heightened during aging, and although the estrogen receptor  (ER) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue ESR1/Esr1 expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ER in fat, we selectively deleted Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, Esr1 was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1. We identified Polg1 as an ER target gene by showing that ER binds the Polg1 promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ER action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.

• Lee-Ødegård, Sindre; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Norheim, Frode; Olsen, Thomas & Refsum, Helga [Show all 9 contributors for this article] (2020). Branched-chain amino acid metabolism, insulin sensitivity and liver fat response to exercise training in sedentary dysglycaemic and normoglycaemic men. Diabetologia. ISSN 0012-186X. 64(2), p. 410–423. doi: 10.1007/s00125-020-05296-0. Full text in Research Archive Show summary

  Aims/hypothesis: Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. Methods: We included 26 sedentary overweight and normal-weight middle-aged men from the MyoGlu clinical trial, with or without dysglycaemia, for 12 weeks of supervised intensive exercise intervention, including two endurance and two resistance sessions weekly. Insulin sensitivity was measured as the glucose infusion rate (GIR) from a hyperinsulinaemic−euglycaemic clamp. In addition, maximum oxygen uptake, upper and lower body strength and adipose tissue depots (using MRI and spectroscopy) were measured, and subcutaneous white adipose tissue (ScWAT) and skeletal muscle (SkM) biopsies were harvested both before and after the 12 week intervention. In the present study we have measured plasma BCAAs and related metabolites using CG-MS/MS and HPLC-MS/MS, and performed global mRNA-sequencing pathway analysis on ScWAT and SkM. Results: In MyoGlu, men with dysglycaemia displayed lower GIR, more fat mass and higher liver fat content than normoglycaemic men at baseline, and 12 weeks of exercise increased GIR, improved body composition and reduced liver fat content similarly for both groups. In our current study we observed higher plasma concentrations of BCAAs (14.4%, p = 0.01) and related metabolites, such as 3-hydroxyisobutyrate (19.4%, p = 0.034) in dysglycaemic vs normoglycaemic men at baseline. Baseline plasma BCAA levels correlated negatively to the change in GIR (ρ = −0.41, p = 0.037) and VO2max (ρ = −0.47, p = 0.015) after 12 weeks of exercise and positively to amounts of intraperitoneal fat (ρ = 0.40, p = 0.044) and liver fat (ρ = 0.58, p = 0.01). However, circulating BCAAs and related metabolites did not respond to 12 weeks of exercise, with the exception of isoleucine, which increased in normoglycaemic men (10 μmol/l, p = 0.01). Pathway analyses of mRNA-sequencing data implied reduced BCAA catabolism in both SkM and ScWAT in men with dysglycaemia compared with men with normoglycaemia at baseline. Gene expression levels related to BCAA metabolism correlated positively with GIR and markers of mitochondrial content in both SkM and ScWAT, and negatively with fat mass generally, and particularly with intraperitoneal fat mass. mRNA-sequencing pathway analysis also implied increased BCAA metabolism after 12 weeks of exercise in both groups and in both tissues, including enhanced expression of the gene encoding branched-chain α-ketoacid dehydrogenase (BCKDH) and reduced expression of the BCKDH phosphatase in both groups and tissues. Gene expression of SLC25A44, which encodes a mitochondrial BCAA transporter, was increased in SkM in both groups, and gene expression of BCKDK, which encodes BCKDH kinase, was reduced in ScWAT in dysglycaemic men. Mediation analyses indicated a pronounced effect of enhanced SkM (~53%, p = 0.022), and a moderate effect of enhanced ScWAT (~18%, p = 0.018) BCAA metabolism on improved insulin sensitivity after 12 weeks of exercise, based on mRNA sequencing. In comparison, plasma concentration of BCAAs did not mediate any effect in this regard. Conclusion/interpretation: Plasma BCAA concentration was largely unresponsive to long-term exercise and unrelated to exercise-induced insulin sensitivity. On the other hand, the insulin-sensitising effect of long-term exercise in men may be explained by enhanced SkM and, to a lesser degree, also by enhanced ScWAT BCAA catabolism.

• Norheim, Frode; Hasin-Brumshtein, Yehudit; Vergnes, Laurent; Krishnan, Karthickeyan Chella; Pan, Calvin & Seldin, Marcus M. [Show all 16 contributors for this article] (2019). Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits. Cell Metabolism. ISSN 1550-4131. 29(4), p. 932–949.e4. doi: 10.1016/j.cmet.2018.12.013. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode; Langleite, Torgrim Mikal; Gulseth, Hanne Løvdal; Birkeland, Kåre I. & Drevon, Christian A (2019). Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight. Diabetologia. ISSN 0012-186X. 62(6), p. 1048–1064. doi: 10.1007/s00125-019-4866-5. Full text in Research Archive Show summary

  Aims/hypothesis Obesity and insulin resistance may be associated with altered expression and secretion of adipokines. Physical activity can markedly improve insulin sensitivity, but the association with adipokines remains largely unknown. In this study, we examined the effects of physical activity on the subcutaneous white adipose tissue (scWAT) secretome and its relationship to insulin sensitivity. Methods As reported previously, we enrolled 26 sedentary, middle-aged men (13 dysglycaemic and overweight; 13 normoglycaemic and of healthy weight) into a 12 week, supervised, intensive physical exercise intervention that included two endurance and two resistance sessions each week. Insulin sensitivity was measured as the glucose infusion rate from a euglycaemic–hyperinsulinaemic clamp. In our previous study, we measured maximum oxygen uptake, upper- and lower-body strength and a range of circulating biomarkers, and quantified adipose tissue depots using MRI and magnetic resonance spectroscopy. We have now performed global mRNA sequencing, microarrays and RT-PCR of scWAT and skeletal muscle biopsies, and quantified selected plasma adipokines by ELISA. Results Insulin sensitivity increased similarly in both dysglycaemic (45%) and normoglycaemic (38%) men after 12 weeks of exercise, as reported previously. mRNA sequencing of scWAT revealed 90 transcripts that responded to exercise in dysglycaemic men, whereas only marginal changes were observed in normoglycaemic men. These results were validated using microarrays and RT-PCR. A total of 62 out of 90 transcripts encoded secreted proteins. Overall, 17 transcripts were upregulated and 73 transcripts were downregulated. Downregulated transcripts included several macrophage markers, and were associated with inflammatory and immune-related pathways. Levels of these immune-related transcripts were enhanced in dysglycaemic men vs normoglycaemic men at baseline, but were normalised after the exercise intervention. Principal component and correlation analyses revealed inverse correlations between levels of these immune-related transcripts and insulin sensitivity at baseline, after the intervention, and for the change between baseline and after the intervention. In addition, levels of these transcripts at baseline could predict exercise-induced improvements in insulin sensitivity. Adipokine levels in scWAT (but not in skeletal muscle) were significantly correlated with corresponding plasma adipokine concentrations, as exemplified by leptin, high-molecular-weight adiponectin and secreted frizzled-related protein 4 (SFRP4). SFRP4 mRNA was the most exercise-responsive transcript in scWAT from dysglycaemic men, and plasma SFRP4 concentrations were reduced in dysglycaemic men, but not in normoglycaemic men, after 12 weeks of exercise. Conclusions/interpretation This study indicates that scWAT may be an important mediator of exercise-induced improvements in insulin sensitivity, especially in overweight dysglycaemic individuals at increased risk of developing type 2 diabetes.

• Norheim, Frode; Bjellaas, Thomas; Hui, Simon T; Krishnan, Karthickeyan Chella; Lee, Jakleen & Gupta, Sonul [Show all 21 contributors for this article] (2018). Genetic, dietary, and sex-specific regulation of hepatic ceramides and relationship between hepatic ceramides and insulin resistance. Journal of Lipid Research. ISSN 0022-2275. 59(7), p. 1164–1174. doi: 10.1194/jlr.M081398. Full text in Research Archive
• Seldin, Marcus M.; Koplev, Simon; Rajbhandari, Prashant; Vergnes, Laurent; Rosenberg, Gregory M & Meng, Yonghong [Show all 27 contributors for this article] (2018). A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metabolism. ISSN 1550-4131. 27(5), p. 1138–1155.e6. doi: 10.1016/j.cmet.2018.03.015. Full text in Research Archive
• Moore, Timothy M.; Zhou, Zhenqi; Cohn, Whitaker; Norheim, Frode; Lin, Amanda J. & Kalajian, Nareg [Show all 23 contributors for this article] (2018). The impact of exercise on mitochondrial dynamics and the role of Drp1 in exercise performance and training adaptations in skeletal muscle. Molecular Metabolism. 21, p. 51–67. doi: 10.1016/j.molmet.2018.11.012. Full text in Research Archive Show summary

  Objective Mitochondria are organelles primarily responsible for energy production, and recent evidence indicates that alterations in size, shape, location, and quantity occur in response to fluctuations in energy supply and demand. We tested the impact of acute and chronic exercise on mitochondrial dynamics signaling and determined the impact of the mitochondrial fission regulator Dynamin related protein (Drp)1 on exercise performance and muscle adaptations to training. Methods Wildtype and muscle-specific Drp1 heterozygote (mDrp1+/−) mice, as well as dysglycemic (DG) and healthy normoglycemic men (control) performed acute and chronic exercise. The Hybrid Mouse Diversity Panel, including 100 murine strains of recombinant inbred mice, was used to identify muscle Dnm1L (encodes Drp1)-gene relationships. Results Endurance exercise impacted all aspects of the mitochondrial life cycle, i.e. fission-fusion, biogenesis, and mitophagy. Dnm1L gene expression and Drp1Ser616 phosphorylation were markedly increased by acute exercise and declined to baseline during post-exercise recovery. Dnm1L expression was strongly associated with transcripts known to regulate mitochondrial metabolism and adaptations to exercise. Exercise increased the expression of DNM1L in skeletal muscle of healthy control and DG subjects, despite a 15% ↓(P = 0.01) in muscle DNM1L expression in DG at baseline. To interrogate the role of Dnm1L further, we exercise trained male mDrp1+/− mice and found that Drp1 deficiency reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training. Conclusion Our findings highlight the importance of mitochondrial dynamics, specifically Drp1 signaling, in the regulation of exercise performance and adaptations to endurance exercise training.

• Lee-Ødegård, Sindre; Norheim, Frode; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Aker, Andreas Helge Mikael & Gundersen, Thomas Erik [Show all 9 contributors for this article] (2018). Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8:6531, p. 1–12. doi: 10.1038/s41598-018-24976-x. Full text in Research Archive Show summary

  Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) composition in skeletal muscle have been linked to insulin sensitivity. We evaluated the relationships between skeletal muscle PC:PE, physical exercise and insulin sensitivity. We performed lipidomics and measured PC and PE in m. vastus lateralis biopsies obtained from 13 normoglycemic normal weight men and 13 dysglycemic overweight men at rest, immediately after 45 min of cycling at 70% maximum oxygen uptake, and 2 h post-exercise, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. Insulin sensitivity was monitored by euglycemic-hyperinsulinemic clamp. RNA-sequencing was performed on biopsies, and mitochondria and lipid droplets were quantified on electron microscopic images. Exercise intervention for 12 w enhanced insulin sensitivity by 33%, skeletal muscle levels of PC by 21%, PE by 42%, and reduced PC:PE by 16%. One bicycle session reduced PC:PE by 5%. PC:PE correlated negatively with insulin sensitivity (β = −1.6, P < 0.001), percent area of mitochondria (ρ = −0.52, P = 0.035), and lipid droplet area (ρ = 0.55, P = 0.017) on EM pictures, and negatively with oxidative phosphorylation and mTOR based on RNA-sequencing. In conclusion, PC and PE contents of skeletal muscle respond to exercise, and PC:PE is inversely related to insulin sensitivity.

• Lee, Sindre; Norheim, Frode; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Kolnes, Kristoffer Jensen & Tangen, Daniel S. [Show all 12 contributors for this article] (2017). Interaction between plasma fetuin-A and free fatty acids predicts changes in insulin sensitivity in response to long-term exercise. Physiological Reports. 5(5). doi: 10.14814/phy2.13183. Full text in Research Archive Show summary

  The hepatokine fetuin‐A can together with free fatty acids (FFAs) enhance adipose tissue (AT) inflammation and insulin resistance via toll‐like receptor 4 (TLR4). Although some of the health benefits of exercise can be explained by altered release of myokines from the skeletal muscle, it is not well documented if some of the beneficial effects of exercise can be explained by altered secretion of hepatokines. The aim of this study was to examine the effect of interaction between fetuin‐A and FFAs on insulin sensitivity after physical exercise. In this study, 26 sedentary men who underwent 12 weeks of combined endurance and strength exercise were included. Insulin sensitivity was measured using euglycemic‐hyperinsulinemic clamp, and AT insulin resistance was indicated by the product of fasting plasma concentration of FFAs and insulin. Blood samples and biopsies from skeletal muscle and subcutaneous AT were collected. Several phenotypic markers were measured, and mRNA sequencing was performed on the biopsies. AT macrophages were analyzed based on mRNA markers. The intervention improved hepatic parameters, reduced plasma fetuin‐A concentration (~11%, P < 0.01), slightly changed FFAs concentration, and improved glucose infusion rate (GIR) (~33%, P < 0.01) across all participants. The change in circulating fetuin‐A and FFAs interacted to predict some of the change in GIR (β = −42.16, P = 0.030), AT insulin resistance (β = 0.579, P = 0.003), gene expression related to TLR‐signaling in AT and AT macrophage mRNA (β = 94.10, P = 0.034) after exercise. We observed no interaction effects between FFAs concentrations and leptin and adiponectin on insulin sensitivity, or any interaction effects between Fetuin‐A and FFAs concentrations on skeletal muscle TLR‐signaling. The relationship between FFAs levels and insulin sensitivity seemed to be specific for fetuin‐A and the AT. Some of the beneficial effects of exercise on insulin sensitivity may be explained by changes in circulating fetuin‐A and FFAs, promoting less TLR4 signaling in AT perhaps by modulating AT macrophages.

• Norheim, Frode; Hui, Simon T; Kulahcioglu, Emre; Mehrabian, Margarete; Cantor, Rita M & Pan, Calvin [Show all 8 contributors for this article] (2017). Genetic and hormonal Control of hepatic steatosis in female and male mice. Journal of Lipid Research. ISSN 0022-2275. p. 178–187. doi: 10.1194/jlr.M071522. Full text in Research Archive Show summary

  The etiology of nonalcoholic fatty liver disease is complex and influenced by factors such as obesity, insulin resistance, hyperlipidemia, and sex. We now report a study on sex difference in hepatic steatosis in the context of genetic variation using a population of inbred strains of mice. While male mice generally exhibited higher concentration of hepatic TG levels on a high-fat high-sucrose diet, sex differences showed extensive interaction with genetic variation. Differences in percentage body fat were the best predictor of hepatic steatosis among the strains and explained about 30% of the variation in both sexes. The difference in percent gonadal fat and HDL explained 9.6% and 6.7% of the difference in hepatic TGs between the sexes, respectively. Genome-wide association mapping of hepatic TG revealed some striking differences in genetic control of hepatic steatosis between females and males. Gonadectomy increased the hepatic TG to body fat percentage ratio among male, but not female, mice. Our data suggest that the difference between the sexes in hepatic TG can be partly explained by differences in body fat distribution, plasma HDL, and genetic regulation. Future studies are required to understand the molecular interactions between sex, genetics, and the environment.

• Langleite, Torgrim Mikal; Jensen, Jørgen; Norheim, Frode; Gulseth, Hanne Løvdal; Tangen, Daniel S. & Kolnes, Kristoffer Jensen [Show all 19 contributors for this article] (2016). Insulin sensitivity, body composition and adipose depots following 12 w combined endurance and strength training in dysglycemic and normoglycemic sedentary men. Archives of Physiology and Biochemistry. ISSN 1381-3455. 122(4), p. 167–179. doi: 10.1080/13813455.2016.1202985. Full text in Research Archive
• Holen, Torgeir; Norheim, Frode; Gundersen, Thomas Erik; Mitry, Patricia; Linseisen, Jakob & Iversen, Per Ole [Show all 7 contributors for this article] (2016). Biomarkers for nutrient intake with focus on alternative sampling techniques. Genes & Nutrition. ISSN 1555-8932. 11:12. doi: 10.1186/s12263-016-0527-1. Full text in Research Archive Show summary

  Biomarkers of nutrient intake or nutrient status are important objective measures of foods/nutrients as one of the most important environmental factors people are exposed to. It is very difficult to obtain accurate data on individual food intake, and there is a large variation of nutrient composition of foods consumed in a population. Thus, it is difficult to obtain precise measures of exposure to different nutrients and thereby be able to understand the relationship between diet, health, and disease. This is the background for investing considerable resources in studying biomarkers of nutrients believed to be important in our foods. Modern technology with high sensitivity and specificity concerning many nutrient biomarkers has allowed an interesting development with analyses of very small amounts of blood or tissue material. In combination with non-professional collection of blood by finger-pricking and collection on filters or sticks, this may make collection of samples and analyses of biomarkers much more available for scientists as well as health professionals and even lay people in particular in relation to the marked trend of self-monitoring of body functions linked to mobile phone technology. Assuming standard operating procedures are used for collection, drying, transport, extraction, and analysis of samples, it turns out that many analytes of nutritional interest can be measured like metabolites, drugs, lipids, vitamins, minerals, and many types of peptides and proteins. The advantage of this alternative sampling technology is that non-professionals can collect, dry, and mail the samples; the samples can often be stored under room temperature in a dry atmosphere, requiring small amounts of blood. Another promising area is the potential relation between the microbiome and biomarkers that may be measured in feces as well as in blood.

• 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
• Lee, Sindre; Norheim, Frode; Langleite, Torgrim Mikal; NORENG, HANS JØRGEN; Storås, Tryggve & Afman, Lydia A. [Show all 18 contributors for this article] (2016). Effect of energy restriction and physical exercise intervention on phenotypic flexibility as examined by transcriptomics analyses of mRNA from adipose tissue and whole body magnetic resonance imaging. Physiological Reports. 4(21). doi: 10.14814/phy2.13019. Full text in Research Archive Show summary

  Overweight and obesity lead to changes in adipose tissue such as inflammation and reduced insulin sensitivity. The aim of this study was to assess how altered energy balance by reduced food intake or enhanced physical activity affect these processes. We studied sedentary subjects with overweight/obesity in two intervention studies, each lasting 12 weeks affecting energy balance either by energy restriction (~20% reduced intake of energy from food) in one group, or by enhanced energy expenditure due to physical exercise (combined endurance‐ and strength‐training) in the other group. We monitored mRNA expression by microarray and mRNA sequencing from adipose tissue biopsies. We also measured several plasma parameters as well as fat distribution with magnetic resonance imaging and spectroscopy. Comparison of microarray and mRNA sequencing showed strong correlations, which were also confirmed using RT‐PCR. In the energy restricted subjects (body weight reduced by 5% during a 12 weeks intervention), there were clear signs of enhanced lipolysis as monitored by mRNA in adipose tissue as well as plasma concentration of free‐fatty acids. This increase was strongly related to increased expression of markers for M1‐like macrophages in adipose tissue. In the exercising subjects (glucose infusion rate increased by 29% during a 12‐week intervention), there was a marked reduction in the expression of markers of M2‐like macrophages and T cells, suggesting that physical exercise was especially important for reducing inflammation in adipose tissue with insignificant reduction in total body weight. Our data indicate that energy restriction and physical exercise affect energy‐related pathways as well as inflammatory processes in different ways, probably related to macrophages in adipose tissue.

• 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
• Hui, Simon T; Parks, Brian W; Org, Elin; Norheim, Frode; Che, Nam & Pan, Calvin [Show all 15 contributors for this article] (2015). The genetic architecture of NAFLD among inbred strains of mice. eLIFE. 4(2015). doi: 10.7554/eLife.05607. Full text in Research Archive Show summary

  To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

• Parks, Brian W; Sallam, Tamer; Mehrabian, Margarete; Psychogios, Nikolas; Hui, Simon T & Norheim, Frode [Show all 21 contributors for this article] (2015). Genetic architecture of insulin resistance in the mouse. Cell Metabolism. ISSN 1550-4131. 21(2), p. 334–346. doi: 10.1016/j.cmet.2015.01.002. 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
• Albrecht, Elke; Norheim, Frode; Thiede, Bernd; Holen, Torgeir; Ohashi, Tomoo & Schering, Lisa [Show all 12 contributors for this article] (2015). Irisin - A myth rather than an exercise-inducible myokine. Scientific Reports. 5. doi: 10.1038/srep08889. 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.

• Li, Yuchuan; Lee, Sindre; Langleite, Torgrim Mikal; Norheim, Frode; Pourteymour, Shirin & Jensen, Jørgen [Show all 13 contributors for this article] (2014). Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention. Physiological Reports. 2(11). doi: 10.14814/phy2.12187. Full text in Research Archive
• 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
• Raschke, Silja; Elsen, Manuela; Gassenhuber, Hans; Sommerfeld, Mark; Schwahn, Uwe & Brockmann, Barbara [Show all 16 contributors for this article] (2013). Evidence against a Beneficial Effect of Irisin in Humans. PLOS ONE. 8(9). doi: 10.1371/journal.pone.0073680. Full text in Research Archive Show summary

  Brown adipose tissue has gained interest as a potential target to treat obesity and metabolic diseases. Irisin is a newly identified hormone secreted from skeletal muscle enhancing browning of white fat cells, which improves systemic metabolism by increasing energy expenditure in mice. The discovery of irisin raised expectations of its therapeutic potential to treat metabolic diseases. However, the effect of irisin in humans is unclear. Analyses of genomic DNA, mRNA and expressed sequence tags revealed that FNDC5, the gene encoding the precursor of irisin, is present in rodents and most primates, but shows in humans a mutation in the conserved start codon ATG to ATA. HEK293 cells transfected with a human FNDC5 construct with ATA as start codon resulted in only 1% full-length protein compared to human FNDC5 with ATG. Additionally, in vitro contraction of primary human myotubes by electrical pulse stimulation induced a significant increase in PGC1a mRNA expression. However, FNDC5 mRNA level was not altered. FNDC5 mRNA expression in muscle biopsies from two different human exercise studies was not changed by endurance or strength training. Preadipocytes isolated from human subcutaneous adipose tissue exhibited differentiation to brite human adipocytes when incubated with bone morphogenetic protein (BMP) 7, but neither recombinant FNDC5 nor irisin were effective. In conclusion, our findings suggest that it is rather unlikely that the beneficial effect of irisin observed in mice can be translated to humans.

• Parks, Brian W.; Nam, Elizabeth; Org, Elin; Kostem, Emrah; Norheim, Frode & Hui, Simon T. [Show all 23 contributors for this article] (2013). Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat, High-Sucrose Diet in Mice. Cell Metabolism. ISSN 1550-4131. 17(1), p. 141–152. doi: 10.1016/j.cmet.2012.12.007. Full text in Research Archive
• Gjelstad, Ingrid Merethe Fange; Haugen, Fred; Gulseth, Hanne Løvdal; Norheim, Frode; Jans, Annike & Bakke, Siril Skaret [Show all 15 contributors for this article] (2012). Expression of perilipins in human skeletal muscle in vitro and in vivo in relation to diet, exercise and energy balance. Archives of Physiology and Biochemistry. ISSN 1381-3455. 118(1), p. 22–30. doi: 10.3109/13813455.2011.630009. Full text in Research Archive
• Hanssen, Knut Egil; Kvamme, Nils Helge; Nilsen, Tormod Skogstad; Rønnestad, Bent; Ambjørnsen, Inger Karine & Norheim, Frode [Show all 10 contributors for this article] (2012). The effect of strength training volume on satellite cells, myogenic regulatory factors, and growth factors. Scandinavian Journal of Medicine & Science in Sports. ISSN 0905-7188. 23(6), p. 728–739. doi: 10.1111/j.1600-0838.2012.01452.x. 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.

• Norheim, Frode; Raastad, Truls; Thiede, Bernd; Rustan, Arild; Drevon, Christian A & Haugen, Fred (2011). Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 301(5), p. E1013–E1021. doi: 10.1152/ajpendo.00326.2011. Full text in Research Archive
• Haugen, Fred; Norheim, Frode; Lian, Henrik; Wensaas, Andreas Johansen; Dueland, Svein & Berg, Ole [Show all 10 contributors for this article] (2010). IL-7 is expressed and secreted by human skeletal muscle cells. American Journal of Physiology - Cell Physiology. 298(4), p. C807–C816. doi: 10.1152/ajpcell.00094.2009. Full text in Research Archive Show summary

  In addition to generating movement, skeletal muscle may have a function as a secretory organ. The aim of the present study was to identify novel proteins with signaling capabilities secreted from skeletal muscle cells. IL-7 was detected in media conditioned by primary cultures of human myotubes differentiated from satellite cells, and concentrations increased with incubation time. By immunoblotting and real-time RT-PCR IL-7 expression was confirmed at both protein and mRNA levels. Furthermore, with immunofluorescence and specific antisera, multinucleated myotubes were found to coexpress IL-7 and myosin heavy chain. During differentiation of human myotubes from satellite cells, IL-7 expression increased at mRNA and protein levels. In contrast, mRNA expression of the IL-7 receptor was 80% lower in myotubes compared with satellite cells. Incubations with recombinant IL-7 under differentiation conditions caused ∼35% reduction in mRNA for the terminal myogenic markers myosin heavy chain 2 (MYH2) and myogenin (MYOG), suggesting that IL-7 may act on satellite cells to inhibit development of the muscle fiber phenotype. Alternative routes of cell development were investigated, and IL-7 increased migration of satellite cells by 40% after 48 h in a Transwell system, whereas cell proliferation remained unchanged. In vivo, real-time RT-PCR analysis of musculus vastus lateralis (n = 10) and musculus trapezius (n = 7) biopsies taken from male individuals undergoing a strength training program demonstrated that after 11 wk mean IL-7 mRNA increased by threefold (P = 0.01) and fourfold (P = 0.04), respectively. In conclusion, we have demonstrated that IL-7 is a novel myokine regulated both in vitro and in vivo, and it may play a role in the regulation of muscle cell development.

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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
• Lee-Ødegård, Sindre; Norheim, Frode Amador; Langleite, Torgrim Mikal; Gulseth, Hanne Løvdal; Birkeland, Kåre Inge & Drevon, Christian A (2022). Correction to: Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight (Diabetologia, (2019), 62, 6, (1048-1064), 10.1007/s00125-019-4866-5). Diabetologia. ISSN 0012-186X. doi: 10.1007/s00125-022-05841-z. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode Amador; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Aker, Andreas Helge Mikael & Gundersen, Thomas Erik [Show all 9 contributors for this article] (2018). Author Correction: Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8(1), p. 7885–7885. doi: 10.1038/s41598-018-26061-9. Full text in Research Archive
• Norheim, Frode; Raastad, Truls; Thiede, Bernd; Drevon, Christian A & Haugen, Fred (2010). The human skeletal muscle secretome - identification of the most abundantly secreted proteins in vitro and their regulation in response to training in vivo. Cardiovascular Research (CVR). ISSN 0008-6363. 87, p. S120–S120. Full text in Research Archive
• Gjelstad, Ingrid Merethe Fange; Norheim, Frode; Raastad, Truls; Birkeland, Kåre I. & Drevon, Christian A (2009). Change in expression levels of lipid droplet coat protein in human skeletal muscle during strength training. Diabetologia. ISSN 0012-186X. 52, p. S270–S270. Full text in Research Archive

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