Sindre Lee-Ødegård

• Bjerkreim, Betty Ann; Hammerstad, Sara Salehi; Lee-Ødegård, Sindre & Eriksen, Erik Fink (2026). Assessment of biomarkers of thyroid hormone action across three thyroid hormone replacement regimens in hypothyroidism. Frontiers in Endocrinology. 17. doi: 10.3389/fendo.2026.1919606. Fulltekst i vitenarkiv
• 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. Fulltekst i vitenarkiv
• Suntharalingam, Anita; Sharma, Archana; Qvigstad, Elisabeth; Sattar, Naveed; Gill, Jason M. R. & Bjørnvall, Christina Dybdrodt [Vis alle 12 forfattere av denne artikkelen] (2025). Differences in tissue-specific insulin resistance between South Asian and Nordic women with prediabetes after gestational diabetes. Diabetologia. ISSN 0012-186X. 68(12), s. 2696–2708. doi: 10.1007/s00125-025-06546-9. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Waage, Christin; Jenum, Anne Karen; Mdala, Ibrahimu; Lee-Ødegård, Sindre; Brænd, Anja Maria & Sletner, Line [Vis alle 8 forfattere av denne artikkelen] (2025). Diabetes and prediabetes among women universally screened for gestational diabetes: a multi-ethnic, population-based, prospective study with eleven years follow-up. BMC Public Health. 25(1). doi: 10.1186/s12889-025-22493-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Gestational diabetes (GDM) is a strong risk factor for later development of diabetes. However, data are scarce on the long-term risk for diabetes or prediabetes diagnosed by HbA1c, in non-selected, multi-ethnic populations universally screened for GDM using the WHO2013 criteria. We aimed to investigate the development of diabetes or prediabetes eleven years after the index pregnancy and identify risk factors in pregnancy or shortly after. Methods A population-based cohort study of 360 women with complete eleven years follow-up data for diabetes (HbA1c≥48 mmol/mol) or prediabetesADA (HbA1c 39–47 mmol/mol). Women were enrolled in gestational week 15 and universally screened with an oral glucose tolerance test in week 28. We performed least absolute shrinkage and selection operator (LASSO) regression to identify predictors of future diabetes or prediabetesADA and constructed a nomogram to predict individual risks. Results Diabetes or prediabetesADA combined, was found in 26.9%, and the prevalence was slightly higher in previous GDM compared with non-GDM women (35.6% versus 23.5%; p=0.019). The relative risk (RR) for developing diabetes or prediabetesADA was moderately elevated in GDM compared with non-GDM women (1.4 [1.0, 1.9], p=0.035). Seven women (1.9%) had diabetes and all of these except for one, had previous GDM. Hence, the crude prevalence was 5.8% among GDM women vs. 0.4% among non-GDM women. The RR for developing diabetes was substantially higher in GDM vs. non-GDM women (14.8 [2.6, 277.1], p=0.012). PrediabetesADA was found in 25% and the RR for prediabetesADA was not significantly increased for GDM compared to non-GDM women (1.3 [0.9, 1.8], p=0.143). Among Europeans, 17.0% had diabetes or prediabetesADA, compared to 43.0% among South Asians (p<0.001) and 34.4% among other ethnicities (p=0.002). The most significant predictors identified from the LASSO were HbA1c measured in early pregnancy, ethnicity, and a family history of diabetes. Conclusions The risk for developing diabetes was low, overall and among GDM women. Still GDM represented a strong risk for diabetes, but not for prediabetesADA. HbA1c early in pregnancy, non-European ethnicity, and a family history of diabetes were the strongest risk factors for developing diabetes or prediabetesADA.

• Bargas, Nicolas Fragoso; Mcbride, Nancy S.; Lee-Ødegård, Sindre; Lawlor, Deborah A.; Yousefi, Paul D. & Moen, Gunn-Helen [Vis alle 14 forfattere av denne artikkelen] (2025). Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes. BMC Genomics. 26. doi: 10.1186/s12864-025-11262-0. Fulltekst i vitenarkiv Vis sammendrag

  Background: Few studies have explored the association between DNA methylation and physical activity. The aim of this study was to evaluate the association of objectively measured hours of sedentary behavior (SB) and moderate physical activity (MPA) with DNA methylation. We further aimed to explore the association between SB or MPA related CpG sites and cardiometabolic traits, gene expression, and genetic variation. Results: For discovery, we performed cross sectional analyses in pregnant women from the Epigenetics in pregnancy (EPIPREG) sample with both DNA methylation (Illumina MethylationEPIC BeadChip) and objectively measured physical activity data (SenseWear™ Pro 3 armband) (European = 244, South Asian = 109). For EWAS of SB and MPA, two main models were designed: model (1) a linear mixed model adjusted for age, smoking, blood cell composition, including ancestry as random intercept, and model (2) which was additionally adjusted for the total number of steps per day. In model 1, we did not identify any CpG sites associated with neither SB nor MPA. In model 2, SB was positively associated (false discovery rate, FDR < 0.05) with two CpG sites within the VSX1 gene. Both CpG sites were positively associated with BMI and were associated with several genetic variants in cis. MPA was associated with 122 significant CpG sites at FDR < 0.05 (model 2). We further analyzed the ten most statistically significant MPA related CpG sites and found that they presented opposite associations with sedentary behavior and BMI. We were not able to replicate the SB and MPA-related CpG sites in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC had available objectively measured physical activity data from Actigraph (without steps/day available) and leucocyte DNA methylation data collected during adolescence (n = 408, European). Conclusion: This study suggests associations of objectively measured SB and MPA with maternal DNA methylation in peripheral blood leukocytes, that needs to be confirmed in larger samples of similar study design.

• Opsahl, Julia Onsrud; Bargas, Nicolas Fragoso; Lee, Y.; Carlsen, E. Ø.; Kiryushchenko, Nadezhda & Qvigstad, E. [Vis alle 13 forfattere av denne artikkelen] (2024). Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain. International Journal of Obesity. ISSN 0307-0565. 48(4), s. 584–593. doi: 10.1038/s41366-024-01458-x. Fulltekst i vitenarkiv Vis sammendrag

  Objectives We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. Methods In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina’s MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). Results We identified one CpG site significantly associated with GWG (p 5.8 × 10−8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10–8 to 2.1 × 10–10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10−8 to 0.04). Conclusions We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits.

• Olsen, Thomas; Stolt, Emma Theresia Kjelland; Øvrebø, Bente; Elshorbagy, Amany; Tore, Elena C. & Lee-Ødegård, Sindre [Vis alle 20 forfattere av denne artikkelen] (2024). Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial. Journal of Translational Medicine. 22(40). doi: 10.1186/s12967-023-04833-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. Methods N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. Results SAAR led to a ~ 20% greater weight loss compared to controls (β 95% CI − 1.14 (− 2.04, − 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. Conclusion Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. Trial registration: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www.clinicaltrials.gov/study/NCT04701346

• Lee-Ødegård, Sindre; Hjorth, Marit; Olsen, Thomas; Moen, Gunn-Helen Øiseth; Daubny, Emily & Evans, David M [Vis alle 17 forfattere av denne artikkelen] (2024). Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis. eLIFE. 13, s. 1–25. doi: 10.7554/ELIFE.96535. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Olsen, Thomas; Vinknes, Kathrine Jørgensen; Barvíková, Kristýna; Stolt, Emma Theresia Kjelland; Lee-Ødegård, Sindre & Troensegaard, Hannibal [Vis alle 18 forfattere av denne artikkelen] (2024). Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression. Redox Biology. 73. doi: 10.1016/j.redox.2024.103192. Fulltekst i vitenarkiv Vis sammendrag

  Background In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. Aim To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. Methods Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. Results SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and β-oxidation (FDR = 0.02). Conclusion SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders.

• Viken, Jonas Krag; Olsen, Thomas; Drevon, Christian André; Hjorth, Marit; Birkeland, Kåre Inge & Norheim, Frode Amador [Vis alle 7 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

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

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

• Borgen, Tove Tveitan; Lee-Ødegård, Sindre; Eriksen, Barbara Fink & Eriksen, Erik Fink (2024). Intermittent Dosing of Zoledronic acid based on bone turnover marker assessment reduces vertebral and non-vertebral fractures. JBMR Plus. 8(7). doi: 10.1093/jbmrpl/ziae072. Fulltekst i vitenarkiv Vis sammendrag

  Previous studies have demonstrated that the administration of zoledronic acid (ZOL) once yearly for 3 years or once over 3 years, yields similar antifracture efficacy. Bone turnover markers can predict the antifracture efficacy of antiresorptive agents, with procollagen type 1 N-terminal propeptide (P1NP) being the most useful marker. In this retrospective cohort study, we explored the effects of intravenous dosing of ZOL guided by serum (S)-P1NP assessment on bone mineral density (BMD) and fractures. Consenting patients (N = 202, mean age 68.2 years) with osteoporosis were treated with ZOL for an average of 4.4 (range 2-8) years. S-P1NP and BMD were measured at baseline and every 1-2 years. We assessed the number of subsequent vertebral and nonvertebral fractures in the 2-year time periods. The number of patients assessed was 202, 147, 69, and 29 at years 1-2, 3-4, 5-6, and 7-8, respectively. A new ZOL infusion was given if S-P1NP exhibited values above 35 μg/L. BMD increased by 6.2% (SD 4.0) over the first 2 years and stabilized in years 2-8 (P <.05). Median S-P1NP exhibited an initial reduction from 58.0 to 31.3 μg/L at year 2 and then increased to 39.0 μg/L at years 7-8. Compared with fractures observed in the last 2 years before baseline, fracture rates exhibited consistent reductions, for vertebral fractures odds ratio (OR) [95% confidence interval] = 0.61 [0.47, 0.80], P <.001 and for nonvertebral fractures OR = 0.23 [0.18, 0.31], P <.001. In conclusion, intermittent dosing of intravenous ZOL based on the assessment of S-P1NP with cut-off at 35 μg/L resulted in an initial increase followed by a stable BMD, suppression of S-P1NP, and stable reduction of fractures for 8 years. Only 39% of patients needed more than one infusion. This approach reduces healthcare costs and might also reduce the risk of rare side effects such as osteonecrosis of the jaw and atypical femoral fracture.

• Sharma, Archana; Birkeland, Kåre Inge; Nermoen, Ingrid; Sommer, Christine; Qvigstad, Elisabeth & Lee-Ødegård, Sindre [Vis alle 11 forfattere av denne artikkelen] (2024). N-terminal pro-B-type natriuretic peptide levels vary by ethnicity and are associated with insulin sensitivity after gestational diabetes mellitus. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02349-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Individuals of South Asian origin have a greater risk of cardiovascular disease after gestational diabetes mellitus (GDM) than European individuals. B-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are commonly used for heart failure screening and diagnosis, but biologically BNP exerts several beneficial cardiovascular effects primarily by counteracting the renin-angiotensin-aldosterone-system. We asked whether ethnic differences in circulating NT-proBNP levels could be explained by the differences in cardiometabolic and inflammatory risk markers? Methods We examined 162 South Asian and 107 Nordic women in Norway 1–3 years after GDM with a clinical examination, fasting blood samples and an oral glucose tolerance test. We measured the levels of NT-proBNP, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, adiponectin and markers of insulin sensitivity, such as the Matsuda insulin sensitivity index (ISI). Finally, we tried to identify which independent covariate best mediated the ethnic differences in NT-proBNP. Results The mean (SD) age was 35.3 (4.5) years, BMI 29.1 (6.0) kg/m2, waist-height ratio 0.60 (0.08) and 164 women (61%) had prediabetes/diabetes. Notably, South Asian women had lower levels of NT-proBNP than Nordic women in both the normoglycemic and prediabetes/diabetes groups (median (IQR) 26  (15–38)  vs. 42 (22–66) ng/L, p < 0.001). Higher NT-proBNP levels were associated with greater insulin sensitivity in both South Asian and Nordic women (p = 0.005 and p < 0.001). South Asian women had higher levels of hsCRP (median (IQR) 2.2 (1.1–4.4) vs. 1.2 (0.3–4.2) mg/L), IL-6 (2.3 (1.5–3.2) vs. 1.5 (1.5–2.5) pg/mL), leptin (1647 (1176–2480) vs. 1223 (876–2313) pmol/L), and lower adiponectin levels (7.2 (5.3–9.3) vs. 10.0 (7.2–13.5) mg/L) and Matsuda ISI (2.4 (1.7–3.7) vs. 4.2 (2.9–6.1), pall<0.01) than Nordic women. Even after adjusting for these differences, higher NT-proBNP levels remained associated with insulin sensitivity (22% higher NT-proBNP per SD Matsuda ISI, p = 0.015). Insulin sensitivity and adiponectin mediated 53% and 41% of the ethnic difference in NT-proBNP. Conclusions NT-proBNP levels are lower in South Asian than in Nordic women after GDM. Lower NT-proBNP levels correlate with impaired insulin sensitivity. Lower NT-proBNP levels in South Asian women could, therefore, be attributed to impaired insulin sensitivity rather than total body fat.

• Grannes, Helene; Sharma, Archana; Suntharalingam, Anita; Michelsen, Annika Elisabet; Aukrust, Pål & Ueland, Thor [Vis alle 10 forfattere av denne artikkelen] (2024). Plasma soluble TIM-3 is increased in normoglycemic South Asian women compared to Nordic women after gestational diabetes mellitus and associated with markers of metaflammation. Heliyon. 10(22). doi: 10.1016/j.heliyon.2024.e40339. Fulltekst i vitenarkiv Vis sammendrag

  Background - Women with South Asian ethnicity have a higher risk of developing type 2 diabetes mellitus (T2DM) compared with white women of European descent, especially after gestational diabetes mellitus (GDM). Central obesity and adipose tissue dysfunction have been linked to their higher risk of T2DM, but the mechanisms are not known. We hypothesize that low-grade, persistent immune cell activation is involved in metabolic disturbances following GDM with different influence according to ethnicity.<p> <p>Methods - We measured plasma levels of T cell exhaustion marker soluble T cell immunoglobin mucin domain 3 (sTIM-3), sCD25, sCD27 and soluble lymphocyte activation gene (sLAG)-3 in 266 women of South Asian (n = 160) and white Nordic (n = 106) ethnic background with a history of GDM.<p> <p>Results - Baseline plasma concentration of sTIM-3 was higher in South Asian women compared to Nordic women (p < 0.001). This difference was driven by higher sTIM-3 in South Asian women with NGT, compared to their Nordic counterparts (p = 0.005) but there were no significant differences comparing Nordic and South Asian women with altered glucose tolerance (AGT). Soluble TIM-3 correlated positively with waist-height ratio (WHtR) and body mass index across all groups, but whereas sTIM-3 correlated moderately and consistently with markers of metaflammation in South Asians, this pattern was not found in Nordic women. Mediation analysis indicated that 15 % of the difference found in adipose insulin resistance between ethnicities could be mediated by sTIM-3, and that 33 % of the difference in sTIM-3 concentrations could be mediated by WHtR. Moreover, T cell markers sCD27 and sLAG3 were also increased in South Asian women compared with Nordic women, further supporting involvement of T cell activation in these women.<p> <p>Conclusion - We found increased levels of sTIM-3, as well as additional markers of T cell activation/exhaustion, in a population of normoglycemic South Asian women with previous gestational diabetes as compared to women of Nordic descent. The possible causal relationship between T cell activation and metabolic dysfunction in high-risk South Asian women is however still elusive and merits further investigation.

• Linares-Pineda, Teresa M.; Bargas, Nicolas Fragoso; Picón, María José; Molina-Vega, Maria; Jenum, Anne Karen & Sletner, Line [Vis alle 14 forfattere av denne artikkelen] (2024). DNA methylation risk score for type 2 diabetes is associated with gestational diabetes. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02151-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria. Methods In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM. Results With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1–1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1–1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM. Conclusion For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.

• Kvist, Ahalya Anita Suntharalingam; Sharma, Archana; Sommer, Christine; Qvigstad, Elisabeth; Gulseth, Hanne Løvdal & Sollid, Stina Therese [Vis alle 12 forfattere av denne artikkelen] (2024). Adipose Tissue Insulin Resistance in South Asian and Nordic Women after Gestational Diabetes Mellitus. Metabolites. 14(5). doi: 10.3390/metabo14050288. Fulltekst i vitenarkiv Vis sammendrag

  South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1–3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs.

• Jersin, Regine Åsen; Tallapragada, Divya Sri; Skartveit, Linn; Bjune, Mona Synnøve; Muniandy, Maheswary & Lee-Ødegård, Sindre [Vis alle 16 forfattere av denne artikkelen] (2023). Impaired Adipocyte SLC7A10 Promotes Lipid Storage in Association With Insulin Resistance and Altered BCAA Metabolism. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 108(9), s. 2217–2229. doi: 10.1210/clinem/dgad148. Fulltekst i vitenarkiv Vis sammendrag

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

• Fragoso-Bargas, Nicolas; Page, Christian Magnus; Joubert, Bonnie R.; London, Stephanie J.; Lee-Ødegård, Sindre & Opsahl, Julia Onsrud [Vis alle 13 forfattere av denne artikkelen] (2023). Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes. Epigenomics. ISSN 1750-1911. 15(1), s. 39–52. doi: 10.2217/epi-2022-0427. Fulltekst i vitenarkiv Vis sammendrag

  Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

• Moore, Timothy M.; Lee-Ødegård, Sindre; Olsen, Thomas; Morselli, Marco; Strumwasser, Alexander R. & Lin, Amanda J. [Vis alle 40 forfattere av denne artikkelen] (2023). Conserved multi-tissue transcriptomic adaptations to exercise training in humans and mice. Cell reports. 42(5). doi: 10.1016/j.celrep.2023.112499. Fulltekst i vitenarkiv Vis sammendrag

  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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Sharma, Archana; Lee-Ødegård, Sindre; Qvigstad, Elisabeth; Sommer, Christine; Sattar, Naveed & Gill, Jason M.R. [Vis alle 10 forfattere av denne artikkelen] (2022). β-Cell Function, Hepatic Insulin Clearance, and Insulin Sensitivity in South Asian and Nordic Women After Gestational Diabetes Mellitus. Diabetes. ISSN 0012-1797. 71(12), s. 2530–2538. doi: 10.2337/db22-0622. Fulltekst i vitenarkiv Vis sammendrag

  South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25–40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.

• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Vis alle 8 forfattere av denne artikkelen] (2022). Fetuin-A mediates the difference in adipose tissue insulin resistance between young adult pakistani and norwegian patients with type 2 diabetes. BMC Endocrine Disorders. 22. doi: 10.1186/s12902-022-01127-y. Fulltekst i vitenarkiv Vis sammendrag

  Background South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR. Aim Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance? Methods We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29–45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans. Results Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients. Conclusion Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

• Doncheva, Atanaska Ivanova; Romero, Silvana Angelica Troncoso; Ramirez-Garrastacho, Manuel; Lee-Ødegård, Sindre; Kolnes, Kristoffer Jensen & Tangen, Daniel S. [Vis alle 11 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Bjerkreim, Betty Ann; Hammerstad, Sara Salehi; Gulseth, Hanne Løvdal; Berg, Tore Julsrud; Lee-Ødegård, Sindre & Eriksen, Erik Fink (2022). Thyroid Signaling Biomarkers in Female Symptomatic Hypothyroid Patients on Liothyronine versus Levothyroxine Monotherapy: A Randomized Crossover Trial. Journal of Thyroid Research. ISSN 2090-8067. 2022. doi: 10.1155/2022/6423023. Fulltekst i vitenarkiv Vis sammendrag

  Background. Levels of thyroid-stimulating hormone (TSH) are believed to reflect degree of disease in patients with hypothyroidism, and normalization of levels is the treatment goal. However, despite adequate levels of TSH after starting levothyroxine (LT4) therapy, 5–10% of hypothyroid patients complain of persisting symptoms with a significant negative impact on quality of life. This indicates that TSH is not an optimal indicator of intracellular thyroid hormone effects in all patients. Our aim was to investigate different effects of LT3 and LT4 monotherapy on other biomarkers of the thyroid signaling pathway, in addition to adverse effects, in patients with residual hypothyroid symptoms. Methods. Fifty-nine female hypothyroid patients, with residual symptoms on LT4 monotherapy or LT4/liothyronine (LT3) combination therapy, were randomly assigned in a non-blinded crossover study and received LT4 or LT3 monotherapy for 12 weeks each. Measurements, including serum analysis of a number of biochemical and hormonal parameters, were obtained at the baseline visit and after both treatment periods. Results. Free thyroxine (FT4) was higher in the LT4 group, while free triiodothyronine (FT3) was higher in the LT3 group. The levels of reverse triiodothyronine (rT3) decreased after LT3 treatment compared with LT4 treatment. Both low-density lipoprotein (LDL) and total cholesterol levels were reduced, while sex hormone-binding globulin (SHBG) increased after LT3 treatment compared with LT4 treatment. The median TSH levels for both treatment groups were within the reference range, however, lower in the LT4 group than in the LT3 group. We did not find any differences in pro-B-type natriuretic peptide (NT pro-BNP), handgrip strength, bone turnover markers, or adverse events between the two treatment groups. Conclusion. We have demonstrated that FT4, FT3, rT3, cholesterol, and SHBG show significantly different values on LT4 treatment compared with LT3 treatment in women with hypothyroidism and residual symptoms despite normal TSH levels. No differences in general or bone-specific adverse effects were demonstrated. This trial is registered with NCT03627611 in May 2018.

• Fragoso-Bargas, Nicolas; Elliott, Hannah R.; Lee-Ødegård, Sindre; Opsahl, Julia Onsrud; Sletner, Line & Jenum, Anne Karen [Vis alle 12 forfattere av denne artikkelen] (2022). Cross-Ancestry DNA Methylation Marks of Insulin Resistance in Pregnancy: An Integrative Epigenome-Wide Association Study. Diabetes. ISSN 0012-1797. 72(3), s. 415–426. doi: 10.2337/db22-0504. Fulltekst i vitenarkiv
• Elshorbagy, Amany; Bastani, Nasser Ezzatkhah; Lee-Ødegård, Sindre; Øvrebø, Bente; Yasein, Nadia Haj & Svendsen, Karianne [Vis alle 10 forfattere av denne artikkelen] (2022). The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression. Amino Acids. ISSN 0939-4451. doi: 10.1007/s00726-022-03229-2. Fulltekst i vitenarkiv Vis sammendrag

  Abstract People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipoprotein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measurements of regional fat, we investigated how cystine compared to other free disulfides in their association with total regional adiposity, plasma lipid and glucose biomarkers, and adipose tissue lipid enzyme mRNA ( n  = 19). Most total plasma homocysteine (tHcy) (78%) was protein-bound; 63% of total glutathione (tGSH) was reduced. tCys was 49% protein-bound, 30% mixed-disulfide, 15% cystine, and 6% reduced. Controlling for age and lean mass, cystine and total free cysteine were the fractions most strongly associated with android and total fat: 1% higher cystine predicted 1.97% higher android fat mass (95% CI 0.64, 3.31) and 1.25% (0.65, 2.98) higher total fat mass (both p  = 0.005). A positive association between tCys and apoB ( β : 0.64%; 95% CI 0.17, 1.12%, p  = 0.009) was apparently driven by free cysteine and cystine; cystine was also inversely associated with the HDL-associated apolipoprotein A1 ( β : −0.57%; 95% CI −0.96, −0.17%, p  = 0.007). No independent positive associations with adiposity were noted for tGSH or tHcy fractions. Plasma cystine correlated with CPT1a mRNA (Spearman’s r  = 0.68, p  = 0.001). In conclusion, plasma cystine—but not homocysteine or glutathione disulfides—is associated with android adiposity and an atherogenic plasma apolipoprotein profile. The role of cystine in human adiposity and cardiometabolic risk deserves investigation. ClinicalTrials.gov identifiers: NCT02647970 and NCT03629392.

• Sommer, Christine; Vangberg, Kjersti G; Moen, Gunn-Helen Øiseth; Evans, David M.; Lee-Ødegård, Sindre & Høgestøl, Ingvild Kristine [Vis alle 11 forfattere av denne artikkelen] (2022). Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 108(5), s. 1110–1119. doi: 10.1210/clinem/dgac699. Fulltekst i vitenarkiv Vis sammendrag

  Context Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. Objective This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. Methods We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. Results In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. Conclusion BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

• Bleskestad, Kristiane Birkeland; Nordheim, Espen; Lindahl, Jørn Petter Hanto; Midtvedt, Karsten; Pihlstrøm, Hege K. & Horneland, Rune [Vis alle 10 forfattere av denne artikkelen] (2021). Insulin secretion and action after pancreas transplantation. A retrospective single-center study. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 81(5), s. 365–370. doi: 10.1080/00365513.2021.1926535. Fulltekst i vitenarkiv Vis sammendrag

  We explored glucometabolic and renal function after engraftment in all 159 consecutive patients with type 1 diabetes who received pancreas transplantation alone (PTA, n = 80) or simultaneous pancreas and kidney transplantation (SPK, n = 79) in Norway from 2012 until 2017. We report fasting levels of plasma glucose (FPG), C-peptide, eGFR and the homeostasis model assessment of insulin sensitivity (HOMA2(%S)) and beta-cell function (HOMA2(%B)) measured one to three times weekly during the first 8 and at 52 weeks after transplantation. One year after engraftment, in the PTA and SPK groups 52 and 64 were normoglycaemic without exogenous insulin, and two and zero patients were dead. Data at the 52-week visit were missing for 5 and 6 patients in the respective groups. During the first 8 weeks, FPG was lower, C-peptide and HOMA2(%S) were higher and eGFR was lower in the SPK group as compared with the PTA group (all p < .05). 30 out of 157 living patients needed insulin treatment 52 weeks after transplantation, 9/79 in the SPK group and 21/78 in the PTA group (p = .02). In conclusion, patients who underwent SPK showed lower insulin sensitivity, but higher insulin secretory capacity and lower mean blood glucose levels the first 8 weeks after transplantation. Also, a higher proportion of patients in the SPK group were insulin-free after 1 year, compared with the PTA group.

• Tallay, Elias; Lindberg, Sondre K.; Lee-Ødegård, Sindre; Bjordal, Jonas; Fraser, Alexander Nilsskog & Madsen, Jan Erik [Vis alle 7 forfattere av denne artikkelen] (2021). External validity in a multicenter randomized clinical trial of proximal humeral fractures: the DelPhi trial. European Journal of Orthopaedic Surgery & Traumatology (EJOST). ISSN 1633-8065. doi: 10.1007/s00590-021-02982-6. Fulltekst i vitenarkiv
• Bjerkreim, Betty Ann; Hammerstad, Sara Salehi; Gulseth, Hanne Løvdal; Berg, Tore Julsrud; Lee-Ødegård, Sindre & Rangberg, Anbjørg [Vis alle 12 forfattere av denne artikkelen] (2021). Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study. Frontiers in Endocrinology. 13, s. 1–11. doi: 10.3389/fendo.2022.816566. Fulltekst i vitenarkiv
• Fragoso-Bargas, Nicolas; Opsahl, Julia Onsrud; Kiryushchenko, Nadezhda; Böttcher, Yvonne; Lee-Ødegård, Sindre & Qvigstad, Elisabeth [Vis alle 15 forfattere av denne artikkelen] (2021). Cohort profile: Epigenetics in Pregnancy (EPIPREG) – Population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes. PLOS ONE. 16(8), s. 1–15. doi: 10.1371/journal.pone.0256158. Fulltekst i vitenarkiv Vis sammendrag

  Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother’s and child’s health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.

• Hansen, Anne-Marte; Wium, Cecilie; Lee-Ødegård, Sindre; Tierney, Audrey C.; McCarthy, Danielle & Roche, Helen M. [Vis alle 9 forfattere av denne artikkelen] (2020). Substantial inter-individual variations in insulin secretion and sensitivity across the glucometabolic spectrum. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 80(4), s. 282–290. doi: 10.1080/00365513.2020.1730433. Fulltekst i vitenarkiv Vis sammendrag

  Impaired insulin secretion and action are important for development of type 2 diabetes (T2D) and metabolic syndrome (MetS). Despite recognized heterogeneity of these glucometabolic disorders, few data are available of biological variation in insulin secretion and action among individuals with T2D and MetS. The aim of this study was to explore the inter-individual variations using gold standard methods in a cross-sectional study of two independent cohorts of phenotypically well-characterized subjects. Cohort I included 486 subjects with MetS, and cohort II 62 subjects with established T2D. First phase insulin secretion was defined as the incremental area under the curve 0–8 min (iAUC0–8 min) during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured as the insulin sensitivity index (SI) modelled from IVGTT in cohort I, and in II as total glucose disposal (TGD) estimated from a euglycaemic-hyperinsulinaemic clamp. Variation is given as total range and, fold-variation between 5%- and 95%-percentile. The iAUC0–8 min ranged from −60 to 3397 mUL−1min−1 among subjects with MetS and from −263 to 1194 mUL−1min−1 in subjects with T2D, representing a more than 10-fold variation. Insulin sensitivity ranged from SI 0.19 to 15.29 (mU/L)−1min−1 among subjects with MetS and TGD 12.9–101.6 μmolkgFFM−1min−1 in subjects with T2D, representing a 6.8 and 5.5-fold variation, respectively. The other components of MetS; BMI, waist-hip ratio, HDL-cholesterol, triglycerides and blood pressure (BP), showed a 1.4–4.7-fold variation. In conclusion, our data demonstrated extensive inter-individual variations in insulin secretion and sensitivity. These variations may be essential to take into account when planning clinical research and treatment in subjects with T2D and MetS.

• Lee, Yunsung; Jacobsen, Kristine Løkås; Denault, William Robert Paul; Nustad, Haakon Egdetveit; Page, Christian & Lyle, Robert [Vis alle 19 forfattere av denne artikkelen] (2020). Blood-based epigenetic estimators of chronological age in human adults using DNA methylation data from the Illumina MethylationEPIC array. BMC Genomics. 21(1). doi: 10.1186/s12864-020-07168-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age. Results We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set. Conclusions Our ABECs predicted adults’ chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.

• Olsen, Thomas; Øvrebø, Bente; Yasein, Nadia Haj; Lee-Ødegård, Sindre; Svendsen, Karianne & Hjorth, Marit [Vis alle 11 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 31 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 9 forfattere av denne artikkelen] (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), s. 410–423. doi: 10.1007/s00125-020-05296-0. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Blakstad, Elin Wahl; Korpela, Katri; Lee-Ødegård, Sindre; Nakstad, Britt; Moltu, Sissel & Strømmen, Kenneth [Vis alle 11 forfattere av denne artikkelen] (2019). Enhanced nutrient supply and intestinal microbiota development in very low birth weight infants. Pediatric Research. ISSN 0031-3998. doi: 10.1038/s41390-019-0412-x. Fulltekst i vitenarkiv
• Lee-Ødegård, Sindre; Olsen, Thomas; Vinknes, Kathrine; Refsum, Helga; Gulseth, Hanne Løvdal & Birkeland, Kåre I. [Vis alle 7 forfattere av denne artikkelen] (2019). Plasma Sulphur-Containing Amino Acids, Physical Exercise and Insulin Sensitivity in Overweight Dysglycemic and Normal Weight Normoglycemic Men. Nutrients. 11(1). doi: 10.3390/nu11010010. Fulltekst i vitenarkiv Vis sammendrag

  Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n = 13) men underwent 45 min cycling before and after 12 weeks exercise intervention. We performed hyperinsulinemic euglycemic clamp, mRNA-sequencing of skeletal muscle and adipose tissue biopsies, and targeted profiling of plasma metabolites by LC-MS/MS. Insulin sensitivity increased similarly in dysglycemic and normoglycemic men after 12 weeks of exercise, in parallel to similar increases in concentration of plasma glutamine, and decreased concentrations of plasma glutamate, cysteine, taurine, and glutathione. Change in plasma concentrations of cysteine and glutathione exhibited the strongest correlations to exercise-improved insulin sensitivity, and expression of a cluster of genes essential for oxidative phosphorylation and fatty acid metabolism in both skeletal muscle and adipose tissue, as well as mitochondria-related genes such as mitofilin. Forty-five min of cycling decreased plasma concentrations of glutamine and methionine, and increased plasma concentrations of glutamate, homocysteine, cystathionine, cysteine, glutathione, and taurine. Similar acute responses were seen in both groups before and after the 12 weeks training period. Both acute and long-term exercise may influence transsulphuration and glutathione biosynthesis, linking exercise-improved insulin sensitivity to oxidative stress and mitochondrial function.

• 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), s. 1048–1064. doi: 10.1007/s00125-019-4866-5. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Lee-Ødegård, Sindre; Kolset, Svein Olav; Birkeland, Kåre I.; Drevon, Christian A & Reine, Trine M. (2019). Acute exercise increases syndecan-1 and -4 serum concentrations. Glycoconjugate Journal. ISSN 0282-0080. 36(2), s. 113–125. doi: 10.1007/s10719-019-09869-z. Fulltekst i vitenarkiv Vis sammendrag

  The effects of acute and long-term exercise on syndecans and the relationship to insulin sensitivity are not fully explored. We aimed to examine the effects of acute and 12 weeks of exercise on (1) serum levels of syndecan-1 and -4, (2) gene expression related to syndecan synthesis and modification in skeletal muscle and adipose tissue, and (3) the relationship to insulin sensitivity. Sedentary men with (n = 13) or without (n = 13) dysglycemia underwent two 45 min acute bicycle tests interspersed by 12 weeks of exercise intervention. Euglycemic hyperinsulinemic clamp and mRNA-sequencing of skeletal muscle and adipose tissue biopsies were performed before and after intervention. Serum syndecan-1 and -4 levels were quantified before, immediately after and 2 h after bicycling. Syndecan-1 and -4 serum concentrations increased in response to acute physical exercise. Baseline syndecan-4 but not syndecan-1 concentrations were higher in dysglycemic compared to normoglycemic men, and correlated to change in insulin sensitivity, but did not change during the 12 weeks exercise intervention. Only syndecan-4 was expressed in skeletal muscle and adipose tissue. Adipose tissue mRNA levels of transcripts affecting syndecan structure and shedding were upregulated in dysglycemia, and muscle mRNA responded to long-term physical activity. The increase in serum syndecan-1 and -4 due to acute exercise suggest increased syndecan shedding and disruption of glycocalyx in response to increased blood flow. The higher syndecan-4 baseline serum levels in dysglycemia, association to insulin sensitivity, and changes in mRNA transcripts may suggest syndecan-4 involvement in muscle and adipose tissue response to exercise.

• Moore, Timothy M.; Zhou, Zhenqi; Cohn, Whitaker; Norheim, Frode; Lin, Amanda J. & Kalajian, Nareg [Vis alle 23 forfattere av denne artikkelen] (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, s. 51–67. doi: 10.1016/j.molmet.2018.11.012. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 9 forfattere av denne artikkelen] (2018). Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8:6531, s. 1–12. doi: 10.1038/s41598-018-24976-x. Fulltekst i vitenarkiv Vis sammendrag

  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. [Vis alle 12 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Pourteymour, Shirin; Eckardt, Kristin; Holen, Torgeir; Langleite, Torgrim Mikal; Lee, Sindre & Jensen, Jørgen [Vis alle 9 forfattere av denne artikkelen] (2017). Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines. Molecular Metabolism. 6(4), s. 352–365. doi: 10.1016/j.molmet.2017.01.007. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Pourteymour, Shirin; Hjorth, Marit; Lee-Ødegård, Sindre; Holen, Torgeir; Langleite, Torgrim Mikal & Jensen, Jørgen [Vis alle 9 forfattere av denne artikkelen] (2017). Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise. Physiological Reports. 5:e13459(19), s. 1–14. doi: 10.14814/phy2.13459. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 11 forfattere av denne artikkelen] (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), s. 45–60. doi: 10.1111/apha.12631. Fulltekst i vitenarkiv
• Lee, Sindre; Norheim, Frode; Langleite, Torgrim Mikal; NORENG, HANS JØRGEN; Storås, Tryggve & Afman, Lydia A. [Vis alle 18 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 16 forfattere av denne artikkelen] (2016). The exercise-regulated myokine chitinase-3-like protein 1 stimulates human myocyte proliferation. Acta Physiologica. ISSN 1748-1708. 216(3), s. 330–345. doi: 10.1111/apha.12579. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 13 forfattere av denne artikkelen] (2015). The effect of acute and long-term physical activity on extracelluar Matrix and serglycin in huuman skeletal muscle. Physiological Reports. 3:e12473(8), s. 1–19. doi: 10.14814/phy2.12473. Fulltekst i vitenarkiv
• Albrecht, Elke; norheim, frode; Thiede, Bernd; Lee, Sindre; Holen, Torgeir & Ohashi,, Tomoo [Vis alle 12 forfattere av denne artikkelen] (2015). Irisin – a myth rather than an exercise-inducible myokine. Scientific Reports. doi: 10.1038/srep08889. Fulltekst i vitenarkiv
• Pourteymour, Shirin; Lee, Sindre; Langleite, Torgrim Mikal; Eckardt, Kristin; Hjorth, Marit & Bindesbøll, Christian [Vis alle 11 forfattere av denne artikkelen] (2015). Perilipin 4 in human skeletal muscle: localization and effect of physical activity. Physiological Reports. 3:e12481(8), s. 1–15. doi: 10.14814/phy2.12481. Fulltekst i vitenarkiv
• Albrecht, Elke; Norheim, Frode; Thiede, Bernd; Holen, Torgeir; Ohashi, Tomoo & Schering, Lisa [Vis alle 12 forfattere av denne artikkelen] (2015). Irisin - A myth rather than an exercise-inducible myokine. Scientific Reports. 5. doi: 10.1038/srep08889. Fulltekst i vitenarkiv
• Li, Yuchuan; Lee, Sindre; Langleite, Torgrim Mikal; Norheim, Frode; Pourteymour, Shirin & Jensen, Jørgen [Vis alle 13 forfattere av denne artikkelen] (2014). Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention. Physiological Reports. 2(11). doi: 10.14814/phy2.12187. Fulltekst i vitenarkiv
• Norheim, Frode; Hjorth, Marit; Langleite, Torgrim Mikal; Lee, Sindre; Holen, Torgeir & Bindesbøll, Christian [Vis alle 13 forfattere av denne artikkelen] (2014). Regulation of angiopoietin-like protein 4 Production during and after exercise. Physiological Reports. 2(8), s. 12–12. doi: 10.14814/phy2.12109. Fulltekst i vitenarkiv
• Kanzleiter, Timo; Rath, Michaela; Görgens, Sven W.; Jensen, Jørgen; Tangen, Daniel S. & Kolnes, Anders Jensen [Vis alle 11 forfattere av denne artikkelen] (2014). The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 450(2), s. 1089–1094. doi: 10.1016/j.bbrc.2014.06.123. Fulltekst i vitenarkiv Vis sammendrag

  The health-promoting effects of regular exercise are well known, and myokines may mediate some of these effects. The small leucine-rich proteoglycan decorin has been described as a myokine for some time. However, its regulation and impact on skeletal muscle has not been investigated in detail. In this study, we report decorin to be differentially expressed and released in response to muscle contraction using different approaches. Decorin is released from contracting human myotubes, and circulating decorin levels are increased in response to acute resistance exercise in humans. Moreover, decorin expression in skeletal muscle is increased in humans and mice after chronic training. Because decorin directly binds myostatin, a potent inhibitor of muscle growth, we investigated a potential function of decorin in the regulation of skeletal muscle growth. In vivo overexpression of decorin in murine skeletal muscle promoted expression of the pro-myogenic factor Mighty, which is negatively regulated by myostatin. We also found Myod1 and follistatin to be increased in response to decorin overexpression. Moreover, muscle-specific ubiquitin ligases atrogin1 and MuRF1, which are involved in atrophic pathways, were reduced by decorin overexpression. In summary, our findings suggest that decorin secreted from myotubes in response to exercise is involved in the regulation of muscle hypertrophy and hence could play a role in exercise-related restructuring processes of skeletal muscle.

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• Bargas, Nicolas Fragoso; Mcbride, Nancy S.; Lee-Ødegård, Sindre; Lawlor, Deborah A.; Yousefi, Paul D. & Moen, Gunn-Helen [Vis alle 14 forfattere av denne artikkelen] (2025). Correction to: Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes (BMC Genomics, (2025), 26, 1, (62), 10.1186/s12864-025-11262-0). BMC Genomics. 26(1). doi: 10.1186/s12864-025-11311-8. Fulltekst i vitenarkiv
• Borgen, Tove Tveitan; Lee-Ødegård, Sindre; Eriksen, Barbara & Eriksen, Erik Fink (2023). Long term treatment with i.v. Zoledronic acid with dosing based on bone turnover markers. Fulltekst i vitenarkiv
• Borgen, Tove Tveitan; Lee-Ødegård, Sindre; Eriksen, Barbara & Eriksen, Erik Fink (2023). Intermittent Dosing of Zoledronic acid Based on Bone Turnover Marker Assessment Reduces Vertebral and Non-Vertebral Fractures. Fulltekst i vitenarkiv
• Elshorbagy, Amany; Bastani, Nasser Ezzatkhah; Lee-Ødegård, Sindre; Øvrebø, Bente; Yasein, Nadia Haj & Svendsen, Karianne [Vis alle 10 forfattere av denne artikkelen] (2023). Correction to: The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression (Amino Acids, (2022), 10.1007/s00726-022-03229-2). Amino Acids. ISSN 0939-4451. 55, s. 547–548. doi: 10.1007/s00726-023-03244-x. Fulltekst i vitenarkiv
• Bargas, Nicolas Fragoso; Linares-Pineda, Teresa; Molina-Vega, María; Picón, María José; Jenum, Anne Karen & Sletner, Line [Vis alle 14 forfattere av denne artikkelen] (2023). Methylation risk score for gestational diabetes on DNA methylation patterns associated with type 2 diabetes. Fulltekst i vitenarkiv
• 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. Fulltekst i vitenarkiv
• Fragoso-Bargas, Nicolas; Lee-Ødegård, Sindre; Moen, Gunn-Helen Øiseth; oppsahl, JO; Sletner, Line & Jenum, Anne Karen [Vis alle 13 forfattere av denne artikkelen] (2022). Epigenome-Wide Association Study of objectively measured moderate physical activity in pregnan. Fulltekst i vitenarkiv Vis sammendrag

  Epigenome-Wide Association Study of objectively measured moderate physical activity in pregnancy Nicolas Fragoso-Bargas1,2, Sindre Lee-Ødegård2, Gunn-Helen Moen2,3,4,5, Julia O. Opsahl2, Line Sletner2,6, Anne Karen Jenum2, Paul Franks7, Rashmi B. Prasad8, Leif C. Groop8, Elisabeth Qvigstad1,2, Kåre I. Birkeland2, Kåre R. Richardsen9, Christine Sommer1 1Oslo University Hospital, Oslo, Norway, 2University of Oslo, Oslo, Norway, 3The University of Queensland Diamantina Institute, Brisbane, Australia, 4Norwegian University of Science and Technology, Trondheim, Norway, 5University of Bristol, UK, 6Akershus University Hospital, Oslo, Norway, 7Lund University Genetic and Molecular Epidemiology, Malmö, Sweden, 8Lund University Diabetes Centre, Malmö, Sweden,9Oslo Metropolitan University, Oslo, Norway. Physical activity (PA) is recommended during pregnancy to reduce the risk of excessive weight gain and gestational diabetes mellitus, and to improve general health. DNA methylation (DNAm) has been proposed as a potential molecular mechanism through which physical activity (PA) mediates the effects on the transcriptome. Here we performed an epigenome-wide association study (EWAS) of objectively measured moderate physical activity in pregnancy, which has not been performed previously. In EPIPREG (a sub-sample of the population-based STORK Groruddalen study) we quantified DNAm at gestational week 28 (±2 SD) with Illumina’s Infinium Methylation EPIC BeadChip. With SenseWear™ Pro3 Armband, we measured hours per day of moderate PA (3.0 to 6.0 metabolic equivalent for task (MET)) and steps/day. DNAm outliers that were 4 times the interquartile range below or above the 25TH and 75TH percentiles respectively were removed, before the beta values were transformed to M-values. Of the 472 that passed the EWAS quality control, 239 European (EUR) and 109 South Asian women (SA) had two valid days of recorded PA (19.2h per day), and were non-outliers (±4 SD) in their respective ethnic group. We used two approaches to test the association between M-values and moderate PA (hours/day): 1) A trans-ethnic approach using mixed linear models adjusted for blood cell proportions, age, smoking, number of steps, number of valid days (between 2 to 8), and ethnicity as a random intercept, and 2) through separate analyses in EUR and SA using linear modelling adjusted with the before mentioned covariates. We accepted a false discovery rate of 10%. In the trans-ethnic analysis, only cg08148261 located in the promoter area of LDHB was significantly associated with moderate PA. In Europeans, eight sites were significant: cg19031974 (BSN-AS2), cg19053287 (MCF2L) cg14930390 (MUTED), cg18517050 (CIAPIN1) and cg26191378 (TMUB1), located near promoter areas, cg27160968 (ESRRA) and cg15879426 (c17orf101) located in exon boundaries, and cg10421808 which is unannotated. In South Asians, only cg05999993 in the promoter area of AOAH was associated with moderate PA. Most of the sites showed decreased DNAm at increased moderate PA (hours/day), while in cg10421808, cg14930390 and cg15879426 the opposite was observed. In conclusion, we found several significant associations between DNAm and moderate PA. Several CpGs were located near gene promoter areas, which could imply altered transcription of the respective genes. These findings suggest that PA may exert changes in DNAm with important transcriptional implications during pregnancy.

• Fragoso-Bargas, Nicolas; Lee-Ødegård, Sindre; Moen, Gunn-Helen Øiseth; Oppsahl, JO; Sletner, Line & Jenum, Anne Karen [Vis alle 12 forfattere av denne artikkelen] (2022). Epigenome-Wide Association Study of objectively measured physical activity in pregnancy. Fulltekst i vitenarkiv
• Lee-Ødegård, Sindre; Norheim, Frode Amador; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Aker, Andreas Helge Mikael & Gundersen, Thomas Erik [Vis alle 9 forfattere av denne artikkelen] (2018). Author Correction: Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8(1), s. 7885–7885. doi: 10.1038/s41598-018-26061-9. Fulltekst i vitenarkiv
• Eckardt, Kristin; Pourteymour, Shirin; Hjorth, Marit; Lee, Sindre; Langleite, Torgrim Mikal & Holen, Torgeir [Vis alle 9 forfattere av denne artikkelen] (2016). Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise. Fulltekst i vitenarkiv
• Eckardt, Kristin; Lee, Sindre; Langleite, Torgrim Mikal; Holen, Torgeir; Jensen, Jørgen & Birkeland, Kåre I. [Vis alle 7 forfattere av denne artikkelen] (2015). Stearoyl-CoA desaturase and its regulation in human skeletal muscle by exercise. Fulltekst i vitenarkiv

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