Christian André Drevon

• Lindstad, Tuva Marie; Pourteymour, Shirin; Lee-Ødegård, Sindre; Drevon, Christian André & Norheim, Frode Amador (2026). Structured Exercise Interventions and Hepatic-Metabolic Outcomes in Adults with MASLD: A Narrative Review of Randomized Controlled Trials. International Journal of Molecular Sciences. ISSN 1661-6596. 27(7). doi: 10.3390/ijms27072941. Full text in Research Archive
• Vetter, Valentin Max; Junge, Marit Philine; Drevon, Christian André; Gundersen, Thomas Erik; Homann, Jan & Lill, Christina M. [Show all 11 contributors for this article] (2026). Comparing fourteen consensus biomarkers of aging: epigenetic pace of aging as the strongest predictor of mortality in BASE-II. Biomarker Research. 14. doi: 10.1186/s40364-026-00909-z. Full text in Research Archive Show summary

  Background In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging. Methods We used data from the Berlin Aging Study II (BASE-II, 60–80 years of age at baseline, average follow-up 7.4 ± 1.5 years, range 3.9–10.4, n = 1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: physiological (insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15)), inflammatory (high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6)), functional (muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty phenotype (FP), cognitive health, blood pressure), and epigenetic (epigenetic clock, DunedinPACE). Cox proportional hazard regression analyses were performed to investigate their role in prediction of all-cause as well as cause-specific mortality. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. Results In adjusted models of all-cause mortality, HGS, IL-6, standing balance, cognitive health, and the epigenetic clock (DunedinPACE) statistically significantly predicted mortality, with the epigenetic clock (DunedinPACE) emerging as the strongest predictor. CRP, gait speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FP and TUG were not associated with mortality in this study. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set consisting of muscle mass, standing balance, and epigenetic clock (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65). Conclusion Among the fourteen investigated biomarkers of aging, DunedinPACE emerged with the strongest and most consistent association with mortality.

• Donado-Pestana, C. M.; Rodrigues, L.; Rundle, M.; Thomas, E. L.; Wopereis, S. & Gundersen, Thomas Erik [Show all 20 contributors for this article] (2025). Plasma metabolomic profiles reveal sex-specific response to an oral glucose tolerance test in late middle-aged adults. Mechanisms of Ageing and Development. ISSN 0047-6374. 226, p. 1–12. doi: 10.1016/j.mad.2025.112081. Full text in Research Archive
• Pourteymour, Shirin; Majhi, Rakesh Kumar; Norheim, Frode Amador & Drevon, Christian André (2025). Exercise Delays Brain Ageing Through Muscle‐Brain Crosstalk. Cell Proliferation. ISSN 0960-7722. 58(7). doi: 10.1111/cpr.70026. Full text in Research Archive Show summary

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

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

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

• Roe, James Michael; Vidal-Piñeiro, Didac; Sørensen, Øystein; Grydeland, Håkon; Leonardsen, Esten Høyland & Iakunchykova, Olena [Show all 35 contributors for this article] (2024). Brain change trajectories in healthy adults correlate with Alzheimer’s related genetic variation and memory decline across life. Nature Communications. 15(1). doi: 10.1038/s41467-024-53548-z. Full text in Research Archive Show summary

  Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer’s disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2–7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer’s Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.

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

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

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

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

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

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

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

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

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

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

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

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

• Ljøsne, Isabelle Sylvie Budin; Friedman, Barbara Bodorkos; Baaré, William F. C.; Bartrés-Faz, David; Carver, Rebecca Bruu & Drevon, Christian André [Show all 17 contributors for this article] (2023). Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium. Health Expectations. ISSN 1369-6513. 26(3), p. 1318–1326. doi: 10.1111/hex.13747. Full text in Research Archive Show summary

  Introduction Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. Methods Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. Results Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. Conclusion Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public Contribution Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

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

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

• Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F C & Bartrés-Faz, David [Show all 21 contributors for this article] (2023). Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers. Journal of Neuroscience. ISSN 0270-6474. 43(28), p. 5241–5250. doi: 10.1523/JNEUROSCI.2330-22.2023. Full text in Research Archive Show summary

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

• Lövden, Martin; Pagin, Amos; Bartres-Faz, David; Boraxbekk, Carl-Johan; Brandmaier, Andreas M. & Demnitz, Naiara [Show all 15 contributors for this article] (2023). No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging. Aging Brain. 4. doi: 10.1016/j.nbas.2023.100082. Full text in Research Archive Show summary

  Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.

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

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

• Strømmen, Kenneth; Lyche, Jan Ludvig; Moltu, Sissel Jennifer; Müller, Mette Helen Bjørge; Blakstad, Elin Wahl & Brække, Kristin [Show all 12 contributors for this article] (2022). Estimated daily intake of phthalates, parabens, and bisphenol A in hospitalised very low birth weight infants. Chemosphere. ISSN 0045-6535. 309(Part 1). doi: 10.1016/j.chemosphere.2022.136687. Full text in Research Archive Show summary

  Very low birth weight infants (VLBW, birth weight (BW) < 1500 g) are exposed to phthalates, parabens and bisphenol A (BPA) early in life. We estimated daily intake (EDI) of these excipients in 40 VLBW infants the first and fifth week of life while hospitalised. Based on urinary samples collected in 2010, EDI was calculated and compared to the tolerable daily intake (TDI) with hazard quotients (HQs) evaluated. A HQ > 1 indicates that EDI exceeded TDI with increased risk of adverse health effects. EDI was higher in VLBW infants compared to term-born infants and older children. VLBW infants born at earlier gestational age (GA), or with lower BW, had higher EDI than infants born at later GA or with higher BW. First week median EDI for BPA was higher than TDI in 100% of infants, in 75% for di(2-ethylhexyl) phthalate (DEHP), 90% for the sum of butyl benzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), DEHP and di-iso-nonyl phthalate (DiNP) = ∑BBzP+DnBP+DEHP+DiNP, and in 50% of infants for propylparaben (PrPa), indicating increased risk of adverse effects. Fifth week EDI remained higher than TDI in all infants for BPA, in 75% for DEHP and ∑BBzP+DnBP+DEHP+DiNP, and 25% of infants for PrPa, indicating prolonged risk. Maximum EDI for di-iso-butyl phthalate was higher than TDI suggesting risk of adverse effects at maximum exposure. VLBW infants born earlier than 28 weeks GA had higher EDI, above TDI, for PrPa compared to infants born later than 28 weeks GA. Infants with late-onset septicaemia (LOS) had higher EDI for DEHP, ∑BBzP+DnBP+DEHP+DiNP and BPA, above TDI, compared to infants without LOS. More 75% of the infants' EDI for DEHP and ∑BBzP+DnBP+DEHP+DiNP, 25% for PrPa, and 100% of infants' EDI for BPA, were above TDI resulting in HQs 1, indicating increased risk of adverse health effects.

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

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

• Carver, Rebecca Bruu; Fredheim, Nanna Alida Grit; Mowinckel, Athanasia Monika; Ebmeier, Klaus P.; Friedman, Barbara Bodorkos & Rosness, Tor Atle [Show all 20 contributors for this article] (2022). People's interest in brain health testing: Findings from an international, online cross-sectional survey. Frontiers in Public Health. 10, p. 1–19. doi: 10.3389/fpubh.2022.998302. Full text in Research Archive Show summary

  Brain health entails mental wellbeing and cognitive health in the absence of brain disorders. The past decade has seen an explosion of tests, cognitive and biological, to predict various brain conditions, such as Alzheimer's Disease. In line with these current developments, we investigated people's willingness and reasons to—or not to—take a hypothetical brain health test to learn about risk of developing a brain disease, in a cross-sectional multilanguage online survey. The survey was part of the Global Brain Health Survey, open to the public from 4th June 2019 to 31st August 2020. Respondents were largely recruited via European brain councils and research organizations. 27,590 people responded aged 18 years or older and were predominantly women (71%), middle-aged or older (>40 years; 83%), and highly educated (69%). Responses were analyzed to explore the relationship between demographic variables and responses. Results: We found high public interest in brain health testing: over 91% would definitely or probably take a brain health test and 86% would do so even if it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those with poor self-reported cognitive health. Conclusion: High public interest in brain health and brain health testing in certain segments of society, coupled with an increase of commercial tests entering the market, is likely to put pressure on public health systems to inform the public about brain health testing in years to come.

• Nyberg, Lars Erik; Andersson, Micael; Lundquist, Anders; Baaré, William F C; Bartrés-Faz, David & Bertram, Lars [Show all 29 contributors for this article] (2022). Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates. Cerebral Cortex. ISSN 1047-3211. 33(9), p. 5075–5081. doi: 10.1093/cercor/bhac400. Full text in Research Archive Show summary

  Abstract It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

• Binnewies, Julia; Nawijn, Laura; Brandmaier, Andreas M.; Baaré, William F.C.; Bartres-Faz, David & Drevon, Christian André [Show all 22 contributors for this article] (2022). Associations of depression and regional brain structure across the adult lifespan: Pooled analyses of six population-based and two clinical cohort studies in the European Lifebrain consortium. NeuroImage: Clinical. 36. doi: 10.1016/j.nicl.2022.103180. Full text in Research Archive
• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Show all 8 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Fiamoncini, Jarlei; Donado-Pestana, Carlos M.; Duarte, Graziela Biude Silva; Rundle, Milena; Thomas, Elizabeth Louise & Kiselova-Kaneva, Yoana [Show all 20 contributors for this article] (2022). Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test. Frontiers in Nutrition. 9. doi: 10.3389/fnut.2022.898782. Full text in Research Archive Show summary

  Insulin secretion following ingestion of a carbohydrate load affects a multitude of metabolic pathways that simultaneously change direction and quantity of interorgan fluxes of sugars, lipids and amino acids. In the present study, we aimed at identifying markers associated with differential responses to an OGTT a population of healthy adults. By use of three metabolite profiling platforms, we assessed these postprandial responses of a total of 202 metabolites in plasma of 72 healthy volunteers undergoing comprehensive phenotyping and of which half enrolled into a weight-loss program over a three-month period. A standard oral glucose tolerance test (OGTT) served as dietary challenge test to identify changes in postprandial metabolite profiles. Despite classified as healthy according to WHO criteria, two discrete clusters (A and B) were identified based on the postprandial glucose profiles with a balanced distribution of volunteers based on gender and other measures. Cluster A individuals displayed 26% higher postprandial glucose levels, delayed glucose clearance and increased fasting plasma concentrations of more than 20 known biomarkers of insulin resistance and diabetes previously identified in large cohort studies. The volunteers identified by canonical postprandial responses that form cluster A may be called pre-pre-diabetics and defined as “at risk” for development of insulin resistance. Moreover, postprandial changes in selected fatty acids and complex lipids, bile acids, amino acids, acylcarnitines and sugars like mannose revealed marked differences in the responses seen in cluster A and cluster B individuals that sustained over the entire challenge test period of 240 min. Almost all metabolites, including glucose and insulin, returned to baseline values at the end of the test (at 240 min), except a variety of amino acids and here those that have been linked to diabetes development. Analysis of the corresponding metabolite profile in a fasting blood sample may therefore allow for early identification of these subjects at risk for insulin resistance without the need to undergo an OGTT.

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

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

• Livingstone, Katherine M.; Brayner, Barbara; Celis-Morales, Carlos; Moschonis, George; Manios, Yannis & Traczyk, Iwona [Show all 15 contributors for this article] (2022). Associations between dietary patterns, FTO genotype and obesity in adults from seven European countries. European Journal of Nutrition. ISSN 1436-6207. 61, p. 2953–2965. doi: 10.1007/s00394-022-02858-3. Full text in Research Archive Show summary

  Purpose High-fat and low-fibre discretionary food intake and FTO genotype are each associated independently with higher risk of obesity. However, few studies have investigated links between obesity and dietary patterns based on discretionary food intake, and the interaction effect of FTO genotype are unknown. Thus, this study aimed to derive dietary patterns based on intake of discretionary foods, saturated fatty acids (SFA) and fibre, and examine cross-sectional associations with BMI and waist circumference (WC), and interaction effects of FTO genotype. Methods Baseline data on 1280 adults from seven European countries were included (the Food4Me study). Dietary intake was estimated from a Food Frequency Questionnaire. Reduced rank regression was used to derive three dietary patterns using response variables of discretionary foods, SFA and fibre density. DNA was extracted from buccal swabs. Anthropometrics were self-measured. Linear regression analyses were used to examine associations between dietary patterns and BMI and WC, with an interaction for FTO genotype. Results Dietary pattern 1 (positively correlated with discretionary foods and SFA, and inversely correlated with fibre) was associated with higher BMI (β:0.64; 95% CI 0.44, 0.84) and WC (β:1.58; 95% CI 1.08, 2.07). There was limited evidence dietary pattern 2 (positively correlated with discretionary foods and SFA) and dietary pattern 3 (positively correlated with SFA and fibre) were associated with anthropometrics. FTO risk genotype was associated with higher BMI and WC, with no evidence of a dietary interaction. Conclusions Consuming a dietary pattern low in discretionary foods and high-SFA and low-fibre foods is likely to be important for maintaining a healthy weight, regardless of FTO predisposition to obesity. Trial registration Clinicaltrials.gov NCT01530139. Registered 9 February 2012 https://clinicaltrials.gov/ct2/show/NCT01530139

• Fragoso-Bargas, Nicolas; Elliott, Hannah R.; Lee-Ødegård, Sindre; Opsahl, Julia Onsrud; Sletner, Line & Jenum, Anne Karen [Show all 12 contributors for this article] (2022). Cross-Ancestry DNA Methylation Marks of Insulin Resistance in Pregnancy: An Integrative Epigenome-Wide Association Study. Diabetes. ISSN 0012-1797. 72(3), p. 415–426. doi: 10.2337/db22-0504. Full text in Research Archive
• Solé-Padullés, Cristina; Macià, Dídac; Andersson, Micael; Stiernstedt, Mikael; Pudas, Sara & Düzel, Sandra [Show all 19 contributors for this article] (2022). No Association Between Loneliness, Episodic Memory and Hippocampal Volume Change in Young and Healthy Older Adults: A Longitudinal European Multicenter Study. Frontiers in Aging Neuroscience. 14. doi: 10.3389/fnagi.2022.795764. Full text in Research Archive Show summary

  Background Loneliness is most prevalent during adolescence and late life and has been associated with mental health disorders as well as with cognitive decline during aging. Associations between longitudinal measures of loneliness and verbal episodic memory and brain structure should thus be investigated. Methods We sought to determine associations between loneliness and verbal episodic memory as well as loneliness and hippocampal volume trajectories across three longitudinal cohorts within the Lifebrain Consortium, including children, adolescents ( N = 69, age range 10–15 at baseline examination) and older adults ( N = 1468 over 60). We also explored putative loneliness correlates of cortical thinning across the entire cortical mantle. Results Loneliness was associated with worsening of verbal episodic memory in one cohort of older adults. Specifically, reporting medium to high levels of loneliness over time was related to significantly increased memory loss at follow-up examinations. The significance of the loneliness-memory change association was lost when eight participants were excluded after having developed dementia in any of the subsequent follow-up assessments. No significant structural brain correlates of loneliness were found, neither hippocampal volume change nor cortical thinning. Conclusion In the present longitudinal European multicenter study, the association between loneliness and episodic memory was mainly driven by individuals exhibiting progressive cognitive decline, which reinforces previous findings associating loneliness with cognitive impairment and dementia.

• Ljøsne, Isabelle Sylvie Budin; Mowinckel, Athanasia Monika; Friedman, Barbara Bodorkos; Ebmeier, Klaus P; Drevon, Christian A & Carver, Rebecca Bruu [Show all 22 contributors for this article] (2022). Public perceptions of brain health: an international, online cross-sectional survey. BMJ Open. 12(4). doi: 10.1136/bmjopen-2021-057999. Full text in Research Archive Show summary

  Objectives To investigate public perspectives on brain health. Design Cross-sectional multilanguage online survey. Setting Lifebrain posted the survey on its website and social media and shared it with stakeholders. The survey was open from 4 June 2019 to 31 August 2020. Participants n=27 590 aged ≥18 years from 81 countries in five continents completed the survey. The respondents were predominantly women (71%), middle aged (41–60 years; 37%) or above (&gt;60 years; 46%), highly educated (69%) and resided in Europe (98%). Main outcome measures Respondents’ views were assessed regarding factors that may influence brain health, life periods considered important to look after the brain and diseases and disorders associated with the brain. We run exploratory linear models at a 99% level of significance to assess correlates of the outcome variables, adjusting for likely confounders in a targeted fashion. Results Of all significant effects, the respondents recognised the impact of lifestyle factors on brain health but had relatively less awareness of the role socioeconomic factors might play. Most respondents rated all life periods as important for the brain (95%–96%), although the prenatal period was ranked significantly lower (84%). Equally, women and highly educated respondents more often rated factors and life periods to be important for brain health. Ninety-nine per cent of respondents associated Alzheimer’s disease and dementia with the brain. The respondents made a connection between mental health and the brain, and mental disorders such as schizophrenia and depression were significantly more often considered to be associated with the brain than neurological disorders such as stroke and Parkinson’s disease. Few respondents (&lt;32%) associated cancer, hypertension, diabetes and arthritis with the brain. Conclusions Differences in perceptions of brain health were noted among specific segments of the population. Policies providing information about brain-friendly health behaviours and targeting people less likely to have relevant experience may be needed.

• Sommer, Christine; Vangberg, Kjersti G; Moen, Gunn-Helen Øiseth; Evans, David M.; Lee-Ødegård, Sindre & Høgestøl, Ingvild Kristine [Show all 11 contributors for this article] (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), p. 1110–1119. doi: 10.1210/clinem/dgac699. Full text in Research Archive Show summary

  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.

• Nyberg, Lars Erik; Magnussen, Fredrik; Lundquist, Anders; Baaré, William; Bartrés-Faz, David & Bertram, Lars [Show all 24 contributors for this article] (2021). Educational attainment does not influence brain aging. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 118(18), p. 1–3. doi: 10.1073/pnas.2101644118. Full text in Research Archive
• Vidal-Piñeiro, Didac; Wang, Yunpeng; Krogsrud, Stine Kleppe; Amlien, Inge; Baaré, William FC & Bartres-Faz, David [Show all 31 contributors for this article] (2021). Individual variations in ‘brain age’ relate to early-life factors more than to longitudinal brain change. eLIFE. 10. doi: 10.7554/eLife.69995. Full text in Research Archive Show summary

  Brain age is a widely used index for quantifying individuals’ brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

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

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

• Wang, Yunpeng; Grydeland, Håkon; Roe, James Michael; Pan, Mengyu; Magnussen, Fredrik & Amlien, Inge [Show all 17 contributors for this article] (2021). Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan. Brain, Behavior, and Immunity. ISSN 0889-1591. 100. doi: 10.1016/j.bbi.2021.12.008. Full text in Research Archive Show summary

  The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers.

• Maak, Steffen; Norheim, Frode Amador; Drevon, Christian A & Erickson, Harold P (2021). Progress and Challenges in the Biology of FNDC5 and Irisin. Endocrine reviews. ISSN 0163-769X. 42(4), p. 436–456. doi: 10.1210/endrev/bnab003. Full text in Research Archive Show summary

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

• Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Alvarez-Alvarez, Ismael; Celis-Morales, Carlos; Livingstone, Katherine M. & O'Donovan, Clare B. [Show all 23 contributors for this article] (2021). Interactions of Carbohydrate Intake and Physical Activity with Regulatory Genes Affecting Glycaemia: A Food4Me Study Analysis. Lifestyle Genomics. ISSN 2504-3161. 14(3), p. 63–72. doi: 10.1159/000515068. Full text in Research Archive Show summary

  Introduction: Carbohydrate intake and physical activity are related to glucose homeostasis, both being influenced by individual genetic makeup. However, the interactions between these 2 factors, as affected by genetics, on glycaemia have been scarcely reported. Objective: We focused on analysing the interplay between carbohydrate intake and physical activity levels on blood glucose, taking into account a genetic risk score (GRS), based on SNPs related to glucose/energy metabolism. Methods: A total of 1,271 individuals from the Food4Me cohort, who completed the nutritional intervention, were evaluated at baseline. We collected dietary information by using an online-validated food frequency questionnaire, a questionnaire on physical activity, blood biochemistry by analysis of dried blood spots, and by analysis of selected SNPs. Fifteen out of 31 SNPs, with recognized participation in carbohydrate/energy metabolism, were included in the component analyses. The GRS included risk alleles involved in the control of glycaemia or energy-yielding processes. Results: Data concerning anthropometric, clinical, metabolic, dietary intake, physical activity, and genetics related to blood glucose levels showed expected trends in European individuals of comparable sex and age, being categorized by lifestyle, BMI, and energy/carbohydrate intakes, in this Food4Me population. Blood glucose was inversely associated with physical activity level (β = −0.041, p = 0.013) and positively correlated with the GRS values (β = 0.015, p = 0.047). Interestingly, an interaction affecting glycaemia, concerning physical activity level with carbohydrate intake, was found (β = −0.060, p = 0.033), which also significantly depended on the genetic background (GRS). Conclusions: The relationships of carbohydrate intake and physical activity are important in understanding glucose homeostasis, where a role for the genetic background should be ascribed.

• Strømmen, Kenneth; Lyche, Jan Ludvig; Moltu, Sissel; Müller, Mette Helen Bjørge; Blakstad, Elin Wahl & Almaas, Astrid Nylander [Show all 12 contributors for this article] (2021). High urinary concentrations of parabens and bisphenol A in very low birth weight infants. Chemosphere. ISSN 0045-6535. 271, p. 1–9. doi: 10.1016/j.chemosphere.2021.129570. Full text in Research Archive Show summary

  Very low birth weight infants (VLBW; birth weight < 1500 g) are treated with pharmaceuticals and medical equipment containing parabens and bisphenol A (BPA). Parabens are used in pharmaceuticals, whereas BPA in medical equipment where concentrations are rarely reported in hospitalised VLBW infants. We measured urinary concentrations of parabens and BPA and hypothesised high and increasing concentrations in infants born at lower gestational ages (GAs), and among infants with bronchopulmonary dysplasia (BPD) and late-onset septicaemia (LOS) due to higher exposure from pharmaceuticals and medical equipment. Urinary samples were collected during the first (n = 38) and fifth (n = 36) week of life. Methylparaben, ethylparaben, propylparaben, butylparaben, and BPA concentrations were measured using ultra high-performance liquid chromatography coupled to tandem mass spectrometry. VLBW infants had very high urinary concentrations of parabens and BPA compared to term infants and older children. The Σ paraben concentration was higher than detected in previous studies on premature infants. Lower GA at birth was associated with higher concentrations of parabens and BPA. Infants born before 28 weeks GA had higher first week concentrations of propylparaben (38.6 vs. 9.05 ng/mL, p = 0.007), butylparaben (0.28 vs. 0.09 ng/mL, p = 0.05) and fifth week concentrations of BPA (15.1 vs. 6.02 ng/mL, p = 0.02) than infants born after 28 weeks GA. Infants with LOS and BPD had higher fifth week concentrations of BPA than infants without LOS and BPD (LOS: 14.2 vs. 6.77 ng/mL, p = 0.07; BPD: 18.6 vs. 7.62 ng/mL, p = 0.05).

• Livingstone, Katherine M.; Celis-Morales, Carlos; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Forster, Hannah & Woolhead, Clara [Show all 24 contributors for this article] (2021). Personalised nutrition advice reduces intake of discretionary foods and beverages: findings from the Food4Me randomised controlled trial. International Journal of Behavioral Nutrition and Physical Activity. 18. doi: 10.1186/s12966-021-01136-5. Full text in Research Archive Show summary

  Background The effect of personalised nutrition advice on discretionary foods intake is unknown. To date, two national classifications for discretionary foods have been derived. This study examined changes in intake of discretionary foods and beverages following a personalised nutrition intervention using these two classifications. Methods Participants were recruited into a 6-month RCT across seven European countries (Food4Me) and were randomised to receive generalised dietary advice (control) or one of three levels of personalised nutrition advice (based on diet [L1], phenotype [L2] and genotype [L3]). Dietary intake was derived from an FFQ. An analysis of covariance was used to determine intervention effects at month 6 between personalised nutrition (overall and by levels) and control on i) percentage energy from discretionary items and ii) percentage contribution of total fat, SFA, total sugars and salt to discretionary intake, defined by Food Standards Scotland (FSS) and Australian Dietary Guidelines (ADG) classifications. Results Of the 1607 adults at baseline, n = 1270 (57% female) completed the intervention. Percentage sugars from FSS discretionary items was lower in personalised nutrition vs control (19.0 ± 0.37 vs 21.1 ± 0.65; P = 0.005). Percentage energy (31.2 ± 0.59 vs 32.7 ± 0.59; P = 0.031), percentage total fat (31.5 ± 0.37 vs 33.3 ± 0.65; P = 0.021), SFA (36.0 ± 0.43 vs 37.8 ± 0.75; P = 0.034) and sugars (31.7 ± 0.44 vs 34.7 ± 0.78; P < 0.001) from ADG discretionary items were lower in personalised nutrition vs control. There were greater reductions in ADG percentage energy and percentage total fat, SFA and salt for those randomised to L3 vs L2. Conclusions Compared with generalised dietary advice, personalised nutrition advice achieved greater reductions in discretionary foods intake when the classification included all foods high in fat, added sugars and salt. Future personalised nutrition approaches may be used to target intake of discretionary foods. Trial registration Clinicaltrials.gov NCT01530139 . Registered 9 February 2012.

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

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

• Walhovd, Kristine Beate; Fjell, Anders Martin; Wang, Yunpeng; Amlien, Inge; Mowinckel, Athanasia Monika & Lindenberger, Ulman [Show all 29 contributors for this article] (2021). Education and income show heterogeneous relationships to lifespan brain and cognitive differences across European and US cohorts. Cerebral Cortex. ISSN 1047-3211. 32(4), p. 839–854. doi: 10.1093/cercor/bhab248. Full text in Research Archive Show summary

  Abstract Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4–97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES–cognition relationships. SES was more strongly related to ICV than to GM, implying that SES–cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES–ICV associations rather are compatible with SES–brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

• Livingstone, Katherine M.; Celis-Morales, Carlos; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Forster, Hannah & Woolhead, Clara [Show all 24 contributors for this article] (2020). Characteristics of participants who benefit most from personalised nutrition: findings from the pan-European Food4Me randomised controlled trial. British Journal of Nutrition. ISSN 0007-1145. 123(12), p. 1396–1405. doi: 10.1017/S0007114520000653. Full text in Research Archive
• Ljøsne, Isabelle Sylvie Budin; Friedman, Barbara Bodorkos; Suri, Sana; Solé-Padullés, Cristina; Düzel, Sandra & Drevon, Christian André [Show all 24 contributors for this article] (2020). The Global Brain Health Survey: Development of a Multi-Language Survey of Public Views on Brain Health. Frontiers in Public Health. doi: 10.3389/fpubh.2020.00387. Full text in Research Archive
• Hansen, Anne-Marte; Wium, Cecilie; Lee-Ødegård, Sindre; Tierney, Audrey C.; McCarthy, Danielle & Roche, Helen M. [Show all 9 contributors for this article] (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), p. 282–290. doi: 10.1080/00365513.2020.1730433. Full text in Research Archive Show summary

  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.

• Ljøsne, Isabelle Sylvie Budin; Friedman, Barbara Bodorkos; Suri, Sana; Solé-Padullés, Cristina; Düzel, Sandra & Drevon, Christian A [Show all 24 contributors for this article] (2020). The global brain health survey: Development of a multi-language survey of public views on brain health. Frontiers in Public Health. 8:387, p. 1–13. doi: 10.3389/fpubh.2020.00387. Full text in Research Archive Show summary

  Background: Brain health is a multi-faceted concept used to describe brain physiology, cognitive function, mental health and well-being. Diseases of the brain account for one third of the global burden of disease and are becoming more prevalent as populations age. Diet, social interaction as well as physical and cognitive activity are lifestyle factors that can potentially influence facets of brain health. Yet, there is limited knowledge about the population's awareness of brain health and willingness to change lifestyle to maintain a healthy brain. This paper introduces the Global Brain Health Survey protocol, designed to assess people's perceptions of brain health and factors influencing brain health. Methods: The Global Brain Health Survey is an anonymous online questionnaire available in 14 languages to anyone above the age of 18 years. Questions focus on (1) willingness and motivation to maintain or improve brain health, (2) interest in learning more about individual brain health using standardized tests, and (3) interest in receiving individualized support to take care of own brain health. The survey questions were developed based on results from a qualitative interview study investigating brain health perceptions among participants in brain research studies. The survey includes 28 questions and takes 15–20 min to complete. Participants provide electronically informed consent prior to participation. The current survey wave was launched on June 4, 2019 and will close on August 31, 2020. We will provide descriptive statistics of samples distributions including analyses of differences as a function of age, gender, education, country of residence, and we will examine associations between items. The European Union funded Lifebrain project leads the survey in collaboration with national brain councils in Norway, Germany, and Belgium, Brain Foundations in the Netherlands and Sweden, the National University of Ostroh Academy and the Women's Brain Project. Discussion: Results from this survey will provide new insights in peoples' views on brain health, in particular, the extent to which the adoption of positive behaviors can be encouraged. The results will contribute to the development of policy recommendations for supporting population brain health, including measures tailored to individual needs, knowledge, motivations and life situations.

• Albrecht, Elke; Schering, Lisa; Buck, Friedrich; Vlach, Konrad; Schober, Hans-Christof & Drevon, Christian A [Show all 7 contributors for this article] (2020). Irisin: Still chasing shadows. Molecular Metabolism. 34, p. 124–135. doi: 10.1016/j.molmet.2020.01.016. Full text in Research Archive Show summary

  Objective Considerable uncertainty remains regarding the veracity of measuring myokine irisin more than seven years after its original description. Unresolved issues include the nature of transcription of the irisin precursor fibronectin type III domain containing 5 (FNDC5) gene across species, the reliability of irisin levels measured with commercial enzyme-linked immunosorbent assays (ELISAs), and the overall validity of the recently published reference values for human serum measured with quantitative mass spectrometry. We utilized multiple species and measures to evaluate the robustness of commonly used reagents and methods for reporting irisin. Methods Amplification of cDNA was used to assess the FNDC5 transcript patterns in humans and mice. The specificity and sensitivity of different irisin antibodies were examined via western blotting. Quantification of circulating native irisin was conducted with mass spectrometry using an absolute quantification peptide for irisin. Results We show that there is a greater transcript diversity of human FNDC5 than currently annotated, but no indication of the expression of transcripts leading to a truncated form of irisin. Available irisin antibodies still bind to patterns of unspecific serum proteins, which compromise reliable measurements of irisin with ELISAs. Absolute quantification of irisin with labeled peptides by mass spectrometry is an advanced method but requires a multi-step sample preparation introducing uncontrollable variations in the measurement. Conclusion Our data represent an explicit warning against measuring circulating irisin using available methods. Measuring irisin is akin to chasing shadows.

• Fjell, Anders Martin; Sørensen, Øystein; Amlien, Inge Kasbohm; Bartrés-Faz, David; Brandmaier, Andreas M. & Buchmann, Nikolaus [Show all 32 contributors for this article] (2020). Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium. Cerebral Cortex. ISSN 1047-3211. p. 1–17. doi: 10.1093/cercor/bhaa332. Full text in Research Archive Show summary

  We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18–92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. “PSQI # 1 Subjective sleep quality” and “PSQI #5 Sleep disturbances” were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with “PSQI #5 Sleep disturbances” emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

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

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

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

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

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

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

• Fjell, Anders Martin; Sørensen, Øystein; Amlien, Inge Kasbohm; Bartrés-Faz, David; Bros, Didac Macia & Buchmann, Nikolaus [Show all 28 contributors for this article] (2019). Self-reported sleep relates to hippocampal atrophy across the adult lifespan – results from the Lifebrain consortium. Sleep. ISSN 0161-8105. doi: 10.1093/sleep/zsz280. Full text in Research Archive Show summary

  Objectives Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan. Methods Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21390 participants from the UK Biobank. Results No cross-sectional sleep – hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses. Conclusions Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.

• Gulseth, Hanne Løvdal; Gjelstad, Ingrid Merethe Fange; Tiereny, Audrey C.; McCarthy, Danielle; Lovegrove, Julie A. & Defoort, Catherine [Show all 13 contributors for this article] (2019). Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome. European Journal of Endocrinology (EJE). ISSN 0804-4643. 180(5), p. 321–328. doi: 10.1530/EJE-19-0022. Full text in Research Archive Show summary

  Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome. In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test. There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010). The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

• Blakstad, Elin Wahl; Korpela, Katri; Lee-Ødegård, Sindre; Nakstad, Britt; Moltu, Sissel & Strømmen, Kenneth [Show all 11 contributors for this article] (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. Full text in Research Archive
• Friedman, Barbara Bodorkos; Suri, Sana; Sole-Padulles, Cristina; Düzel, Sandra; Drevon, Christian A & Baaré, William F. C. [Show all 16 contributors for this article] (2019). Are People Ready for Personalized Brain Health? Perspectives of Research Participants in the Lifebrain Consortium. The gerontologist. ISSN 0016-9013. doi: 10.1093/geront/gnz155. Full text in Research Archive Show summary

  Background and Objectives A healthy brain is central to physical and mental well-being. In this multi-site, qualitative study, we investigated views and attitudes of adult participants in brain research studies on the brain and personalized brain health as well as interest in maintaining a healthy brain. Design and Methods We conducted individual interviews with 44 adult participants in brain research cohorts of the Lifebrain consortium in Spain, Norway, Germany, and the United Kingdom. The interviews were audio recorded, transcribed, and coded using a cross-country codebook. The interview data were analyzed using qualitative content analysis. Most participants did not focus on their own brain health and expressed uncertainty regarding how to maintain it. Those actively focusing on brain health often picked one specific strategy like diet or memory training. The participants were interested in taking brain health tests to learn about their individual risk of developing brain diseases, and were willing to take measures to maintain their brain health if personalized follow-up was provided and the measures had proven impact. The participants were interested in more information on brain health. No differences in responses were identified between age groups, sex, or countries. Discussion and Implications Concise, practical, personalized, and evidence-based information about the brain may promote brain health. Based on our findings, we have launched an ongoing global brain health survey to acquire more extensive, quantitative, and representative data on public perception of personalized brain health.

• Celis-Morales, Carlos; Livingstone, Katherine M.; Petermann-Rocha, Fanny; Navas-Carretero, Santiago; San-Cristobal, Rodrigo & O'Donovan, Clare B. [Show all 22 contributors for this article] (2019). Frequent nutritional feedback, personalized advice, and behavioral changes: Findings from the European Food4Me Internet-Based RCT. American Journal of Preventive Medicine. ISSN 0749-3797. 57(2), p. 209–219. doi: 10.1016/j.amepre.2019.03.024. Full text in Research Archive
• Lee-Ødegård, Sindre; Olsen, Thomas; Vinknes, Kathrine; Refsum, Helga; Gulseth, Hanne Løvdal & Birkeland, Kåre I. [Show all 7 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Aryal, Sanjay; Hussain, Suleman; Drevon, Christian A; Nagelhus, Erlend Arnulf; Hvalby, Øyvind & Jensen, Vidar [Show all 8 contributors for this article] (2019). Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses. European Journal of Neuroscience. ISSN 0953-816X. 49(1), p. 40–50. doi: 10.1111/ejn.14224. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode; Langleite, Torgrim Mikal; Gulseth, Hanne Løvdal; Birkeland, Kåre I. & Drevon, Christian A (2019). Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight. Diabetologia. ISSN 0012-186X. 62(6), p. 1048–1064. doi: 10.1007/s00125-019-4866-5. Full text in Research Archive Show summary

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

• Olsen, Thomas; Vinknes, Kathrine; Blomhoff, Rune; Lysne, Vegard; Midttun, Øivind & Dhar, Indu [Show all 12 contributors for this article] (2019). Creatinine, total cysteine and uric acid are associated with serum retinol in patients with cardiovascular disease. European Journal of Nutrition. ISSN 1436-6207. doi: 10.1007/s00394-019-02086-2. Full text in Research Archive Show summary

  Purpose: We hypothesized that biomarkers and dietary factors related to cardiovascular disease risk were associated with serum retinol and evaluated these potential associations in patients with suspected coronary artery disease (CAD). Methods: We used cross-sectional data from 4116 patients hospitalised for suspected CAD. Dietary data were obtained from a subgroup of 1962 patients using a food frequency questionnaire. Potential biomarkers and dietary factors were explored using linear regression modelling adjusted for age and sex. Regression coefficients and corresponding confidence intervals (CI) are given as % change in serum retinol per unit change in the predictors. Analyses were performed in the total population and in strata of serum retinol tertiles. Results: In age- and sex-adjusted models, serum creatinine (standardized β: 0.38, 95% CI [0.35, 0.42]), plasma total cysteine (0.26, [0.23, 0.29]), serum uric acid (0.30, [0.26, 0.33]) and plasma neopterin (0.22, [0.18, 0.25]) were positively associated, whereas plasma serine (− 0.15, [− 0.18, − 0.12]) and serum C-reactive protein (− 0.15, [− 0.18, − 0.12]) were inversely associated with serum retinol. When we included the significant biomarkers in a multivariate model, the model explained 33% of the variability (R2 = 0.33) in serum retinol. The results were similar in the lower and upper tertiles of serum retinol. Weak or no associations were observed for dietary factors. Conclusions: In patients with suspected CAD, concentrations of creatinine, cysteine and uric acid were positively associated with serum retinol. Future studies should assess whether retinol concentrations are influenced by metabolic alterations in patients at risk of cardiovascular disease.

• 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), p. 113–125. doi: 10.1007/s10719-019-09869-z. Full text in Research Archive Show summary

  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.

• Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Livingstone, Katherine M.; Celis-Morales, Carlos; Marsaux, Cyril F. & Macready, Anna L. [Show all 24 contributors for this article] (2018). Higher vegetable protein consumption, assessed by an isoenergetic macronutrient exchange model, is associated with a lower presence of overweight and obesity in the web-based Food4me European study. International Journal of Food Sciences and Nutrition. ISSN 0963-7486. 70(2), p. 240–253. doi: 10.1080/09637486.2018.1492524. Full text in Research Archive
• Norheim, Frode; Bjellaas, Thomas; Hui, Simon T; Krishnan, Karthickeyan Chella; Lee, Jakleen & Gupta, Sonul [Show all 21 contributors for this article] (2018). Genetic, dietary, and sex-specific regulation of hepatic ceramides and relationship between hepatic ceramides and insulin resistance. Journal of Lipid Research. ISSN 0022-2275. 59(7), p. 1164–1174. doi: 10.1194/jlr.M081398. Full text in Research Archive
• Fallaize, Rosalind; Livingstone, Katherine M.; Celis-Morales, Carlos; Macready, Anna L.; San-Cristobal, Rodrigo & Navas-Carretero, Santiago [Show all 24 contributors for this article] (2018). Association between diet-quality scores, adiposity and biomarkers of cardiometabolic risk in European adults: findings from the Food4Me study. Nutrients. 10(1). doi: 10.3390/nu10010049. Full text in Research Archive Show summary

  Diet-quality scores (DQS), which are developed across the globe, are used to define adherence to specific eating patterns and have been associated with risk of coronary heart disease and type-II diabetes. We explored the association between five diet-quality scores (Healthy Eating Index, HEI; Alternate Healthy Eating Index, AHEI; MedDietScore, MDS; PREDIMED Mediterranean Diet Score, P-MDS; Dutch Healthy Diet-Index, DHDI) and markers of metabolic health (anthropometry, objective physical activity levels (PAL), and dried blood spot total cholesterol (TC), total carotenoids, and omega-3 index) in the Food4Me cohort, using regression analysis. Dietary intake was assessed using a validated Food Frequency Questionnaire. Participants (n = 1480) were adults recruited from seven European Union (EU) countries. Overall, women had higher HEI and AHEI than men (p < 0.05), and scores varied significantly between countries. For all DQS, higher scores were associated with lower body mass index, lower waist-to-height ratio and waist circumference, and higher total carotenoids and omega-3-index (p trends < 0.05). Higher HEI, AHEI, DHDI, and P-MDS scores were associated with increased daily PAL, moderate and vigorous activity, and reduced sedentary behaviour (p trend < 0.05). We observed no association between DQS and TC. To conclude, higher DQS, which reflect better dietary patterns, were associated with markers of better nutritional status and metabolic health.

• Seldin, Marcus M.; Koplev, Simon; Rajbhandari, Prashant; Vergnes, Laurent; Rosenberg, Gregory M & Meng, Yonghong [Show all 27 contributors for this article] (2018). A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metabolism. ISSN 1550-4131. 27(5), p. 1138–1155.e6. doi: 10.1016/j.cmet.2018.03.015. Full text in Research Archive
• Korpela, Katri; Blakstad, Elin Wahl; Moltu, Sissel; Strømmen, Kenneth; Nakstad, Britt & Rønnestad, Arild Erlend [Show all 10 contributors for this article] (2018). Intestinal microbiota development and gestational age in preterm neonates. Scientific Reports. 8:2453, p. 1–9. doi: 10.1038/s41598-018-20827-x. Full text in Research Archive Show summary

  The intestinal microbiota is an important contributor to the health of preterm infants, and may be destabilized by a number of environmental factors and treatment modalities. How to promote the development of a healthy microbiota in preterm infants is largely unknown. We collected fecal samples from 45 breastfed preterm very low birth weight (birth weight<1500g) infants from birth until 60 days postnatal age to characterize the intestinal microbiota development during the frst weeks of life in preterm infants. Fecal microbiota composition was determined by 16S rRNA amplicon sequencing. The main driver of microbiota development was gestational age; antibiotic use had strong but temporary efects and birth mode had little infuence. Microbiota development proceeded in four phases indicated by the dominance of Staphylococcus, Enterococcus, Enterobacter, and fnally Bifdobacterium. The Enterococcus phase was only observed among the extremely premature infants and appeared to delay the microbiota succession. The results indicate that hospitalized preterm infants receiving breast milk may develop a normal microbiota resembling that of term infants.

• Moore, Timothy M.; Zhou, Zhenqi; Cohn, Whitaker; Norheim, Frode; Lin, Amanda J. & Kalajian, Nareg [Show all 23 contributors for this article] (2018). The impact of exercise on mitochondrial dynamics and the role of Drp1 in exercise performance and training adaptations in skeletal muscle. Molecular Metabolism. 21, p. 51–67. doi: 10.1016/j.molmet.2018.11.012. Full text in Research Archive Show summary

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

• Rosendahl-Riise, Hanne; Sulo, Gerhard; Karlsson, Therese; Drevon, Christian A; Dierkes, Jutta & Tell, Grethe S. (2018). Limited benefit of fish consumption on risk of hip fracture among men in the community-based Hordaland health study. Nutrients. 10(7). doi: 10.3390/nu10070873. Full text in Research Archive Show summary

  Hip fractures have a high prevalence worldwide. Few studies have investigated whether fish consumption is associated with risk of hip fractures. The objective of the present study was to investigate the effect of fish intake on the subsequent risk of a hip fracture because of the low number of studies on this topic. A community-based prospective cohort study of 2865 men and women from Hordaland county in Norway, born between 1925–1927 and enrolled in the study in 1997–1999. Information on hip fracture cases was extracted from hospital records until 31 December 2009. Baseline information on the intake of fish was obtained from a semi-quantitative food frequency questionnaire. Cox proportional hazard regression models with death as a competing risk were used to evaluate the association of fish intake with risk of hip fracture. During a mean (SD) follow-up time of 9.6 (2.7) years, 226 hip fractures (72 in men, 154 in women) were observed. The mean (SD) fish intake was 48 (25) g/1000 kcal. The association between fish intake and risk of hip fracture was not linear and displayed a threshold, with low intake of fish being associated with an increased risk of hip fracture in men (HR (Hazard Ratio) = 1.84, 95% CI 1.10, 3.08). In this community-based prospective study of men and women, a low intake of fish was associated with the risk of a hip fracture in men.

• Wanders, Anne J.; Alssema, Marjan; Hoon, Sabine E.M. De; Feskens, Edith J.M.; Woudenbergh, Geertruida J. van & Kallen, Carla J. Van Der [Show all 14 contributors for this article] (2018). Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies. Annals of Nutrition and Metabolism. ISSN 0250-6807. 72(2), p. 117–125. doi: 10.1159/000486244. Full text in Research Archive
• Walhovd, Kristine B; Fjell, Anders Martin; Westerhausen, Rene; Nyberg, L; Ebmeier, K.P. & Lindenberger, U. [Show all 18 contributors for this article] (2018). Healthy minds from 0-100 years: Optimising the use of European brain imaging cohorts ("Lifebrain"). European psychiatry. ISSN 0924-9338. 47, p. 76–87. doi: 10.1016/j.eurpsy.2017.10.005. Full text in Research Archive
• Rosendahl-Riise, Hanne; Karlsson, Therese; Drevon, Christian A; Apalset, Ellen M; Nygård, Ottar & Tell, Grethe S. [Show all 7 contributors for this article] (2018). Total and lean fish intake is positively associated with bone mineral density in older women in the community-based Hordaland Health Study. European Journal of Nutrition. ISSN 1436-6207. p. 1–11. doi: 10.1007/s00394-018-1665-6. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Aker, Andreas Helge Mikael & Gundersen, Thomas Erik [Show all 9 contributors for this article] (2018). Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8:6531, p. 1–12. doi: 10.1038/s41598-018-24976-x. Full text in Research Archive Show summary

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

• Puaschitz, Nathalie Genevieve; Assmus, Jörg; Strand, Elin; Karlsson, Therese; Vinknes, Kathrine & Lysne, Vegard [Show all 10 contributors for this article] (2018). Adherence to the Healthy Nordic Food Index and the incidence of acute myocardial infarction and mortality among patients with stable angina pectoris. Journal of human nutrition and dietetics. ISSN 0952-3871. 32, p. 86–97. doi: 10.1111/jhn.12592. Full text in Research Archive Show summary

  Background: The Healthy Nordic Food Index (HNFI) has been associated with beneficial effects on markers of cardiovascular disease (CVD). Whether such effects are present among patients with established coronary heart disease is unknown. In the present study, we investigated the association between adherence to the HNFI and the risk of acute myocardial infarction (AMI) (fatal or nonfatal) and death among patients with stable angina pectoris. Methods: In the Western Norway B‐vitamin Intervention Trial, participants completed a 169‐item semi‐quantitative food frequency questionnaire. The HNFI was calculated from six food groups (fish, cabbage, apples/pears, root vegetables, whole grain bread and oatmeal), scoring 0–6. Three adherence groups were defined: 0–1 points (low), 2–3 points (medium) or 4–6 points (high). Cox regression analyses investigated associations between adherence to the HNFI and outcomes. Results: Among 2019 men (79.7%) and women with mean age of 61.7 years, 307 patients experienced an AMI event during a median (25th and 75th percentiles) follow‐up of 7.5 (6.3 and 8.7) years. Median follow‐up for total mortality was 10.5 (9.3 and 11.7) years; 171 patients died from CVD and 380 from any cause. No association between HNFI and the risk of AMI was detected. However, the HNFI was associated with a reduced risk of all‐cause death, both by linear estimates [hazard ratio (95% confidence interval = 0.91 (0.84–0.98)] and by comparison of the highest with the lowest adherence group [hazard ratio (95% confidence interval = 0.70 (0.52–0.95)]. Conclusions: The results of the present study suggest that a Healthy Nordic diet may reduce mortality in patients with established CVD.

• Sommer, Christine; Lee, Sindre; Gulseth, Hanne Løvdal; Jensen, Jørgen; Drevon, Christian A & Birkeland, Kåre I. (2018). Soluble leptin receptor predicts insulin sensitivity and correlates with upregulation of metabolic pathways in men. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 103(3), p. 1024–1032. doi: 10.1210/jc.2017-02126. Full text in Research Archive
• Celis-Morales, Carlos; Marsaux, Cyril F.M.; Livingstone, Katherine M.; Navas-Carretero, Santiago; San-Cristobal, Rodrigo & Fallaize, Rosalind [Show all 28 contributors for this article] (2017). Can genetic-based advice help you lose weight? Findings from the Food4Me European randomized controlled trial. American Journal of Clinical Nutrition. ISSN 0002-9165. 105(5), p. 1204–1213. doi: 10.3945/ajcn.116.145680. Full text in Research Archive
• Olsen, Thomas; Vinknes, Kathrine; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Tell, Grethe S. & Blomhoff, Rune [Show all 11 contributors for this article] (2017). Cardiovascular disease risk associated with serum apolipoprotein B is modified by serum vitamin A. Atherosclerosis. ISSN 0021-9150. p. 325–330. doi: 10.1016/j.atherosclerosis.2017.07.020. Full text in Research Archive
• Lee, Sindre; Norheim, Frode; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Kolnes, Kristoffer Jensen & Tangen, Daniel S. [Show all 12 contributors for this article] (2017). Interaction between plasma fetuin-A and free fatty acids predicts changes in insulin sensitivity in response to long-term exercise. Physiological Reports. 5(5). doi: 10.14814/phy2.13183. Full text in Research Archive Show summary

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

• Brouwer-Brolsma, Elske M.; Brennan, Lorraine; Drevon, Christian A; Kranen, Henk Van; Manach, Claudine & Dragsted, Lars Ove [Show all 26 contributors for this article] (2017). Combining traditional dietary assessment methods with novel metabolomics techniques: Present efforts by the Food Biomarker Alliance. Proceedings of the Nutrition Society. ISSN 0029-6651. 76(4), p. 619–627. doi: 10.1017/S0029665117003949. Full text in Research Archive
• Karlsson, Therese; Strand, Elin; Dierkes, Jutta; Drevon, Christian A; Øyen, Jannike & Midttun, Øivind [Show all 10 contributors for this article] (2017). Associations between intake of fish and n-3 long-chain polyunsaturated fatty acids and plasma metabolites related to the kynurenine pathway in patients with coronary artery disease. European Journal of Nutrition. ISSN 1436-6207. 56(1), p. 261–272. doi: 10.1007/s00394-015-1077-9. Full text in Research Archive
• Lund, Jenny; Rustan, Arild; Løvsletten, Nils Gunnar; Mudry, Jonathan M.; Langleite, Torgrim Mikal & Feng, Yuan Zeng [Show all 19 contributors for this article] (2017). Exercise in vivo marks human myotubes in vitro: Training-induced increase in lipid metabolism. PLOS ONE. 12:e0175441(4), p. 1–24. doi: 10.1371/journal.pone.0175441. Full text in Research Archive Show summary

  Background and aims: Physical activity has preventive as well as therapeutic benefits for overweight subjects. In this study we aimed to examine effects of in vivo exercise on in vitro metabolic adaptations by studying energy metabolism in cultured myotubes isolated from biopsies taken before and after 12 weeks of extensive endurance and strength training, from healthy sedentary normal weight and overweight men. Methods: Healthy sedentary men, aged 40–62 years, with normal weight (body mass index (BMI) < 25 kg/m2) or overweight (BMI ≥ 25 kg/m2) were included. Fatty acid and glucose metabolism were studied in myotubes using [14C]oleic acid and [14C]glucose, respectively. Gene and protein expressions, as well as DNA methylation were measured for selected genes. Results: The 12-week training intervention improved endurance, strength and insulin sensitivity in vivo, and reduced the participants’ body weight. Biopsy-derived cultured human myotubes after exercise showed increased total cellular oleic acid uptake (30%), oxidation (46%) and lipid accumulation (34%), as well as increased fractional glucose oxidation (14%) compared to cultures established prior to exercise. Most of these exercise-induced increases were significant in the overweight group, whereas the normal weight group showed no change in oleic acid or glucose metabolism. Conclusions: 12 weeks of combined endurance and strength training promoted increased lipid and glucose metabolism in biopsy-derived cultured human myotubes, showing that training in vivo are able to induce changes in human myotubes that are discernible in vitro.

• Manios, Yannis; Moschonis, George; Lambrinou, Christina P.; Mavrogianni, Christina; Tsirigoti, Lydia & Hoeller, Ulrich [Show all 37 contributors for this article] (2017). Associations of vitamin D status with dietary intakes and physical activity levels among adults from seven European countries: the Food4Me study. European Journal of Nutrition. ISSN 1436-6207. Published ahead of print, p. 1–12. doi: 10.1007/s00394-017-1415-1. Full text in Research Archive
• Albani, Viviana; Celis-Morales, Carlos; O'Donovan, Clare B; Walsh, Marianne C; Woolhead, Clara & Forster, Hannah [Show all 30 contributors for this article] (2017). Within-person reproducibility and sensitivity to dietary change of C15:0 and C17:0 levels in dried blood spots: Data from the European Food4Me Study. Molecular Nutrition & Food Research. ISSN 1613-4125. 61(10). doi: 10.1002/mnfr.201700142. Full text in Research Archive
• Pourteymour, Shirin; Eckardt, Kristin; Holen, Torgeir; Langleite, Torgrim Mikal; Lee, Sindre & Jensen, Jørgen [Show all 9 contributors for this article] (2017). Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines. Molecular Metabolism. 6(4), p. 352–365. doi: 10.1016/j.molmet.2017.01.007. Full text in Research Archive Show summary

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

• San-Cristobal, R; Navas-Carretero, S; Celis-Morales, C; Livingstone, KM; Stewart-Knox, B & Rankin, A [Show all 28 contributors for this article] (2017). Capturing health and eating status through a nutritional perception screening questionnaire (NPSQ9) in a randomised internet-based personalised nutrition intervention: the Food4Me study. International Journal of Behavioral Nutrition and Physical Activity. 11(14), p. 168–168. doi: 10.1186/s12966-017-0624-6. Full text in Research Archive Show summary

  Background National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet. Methods Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively. Results A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (β = −0.181, p < 0.001) and waist circumference (Β = −0.155, p < 0.001), and positively associated with total carotenoids (β = 0.198, p < 0.001), omega-3 fatty acid index (β = 0.155, p < 0.001), Healthy Eating Index (HEI) (β = 0.299, p < 0.001) and Mediterranean Diet Score (MDS) (β = 0. 279, p < 0.001). Findings from the longitudinal intervention study showed a greater reduction in BMI and improved dietary indices among participants with lower NPSQ9 scores. Conclusions Healthy eating perceptions and dietary habits captured by the NPSQ9 score, based on nine questionnaire items, were associated with reduced body weight and improved diet quality. Likewise, participants with a lower score achieved greater health improvements than those with higher scores, in response to personalised advice, suggesting that NPSQ9 may be used for early evaluation of nutritional status and to tailor nutritional advice. Trial registration NCT01530139 .

• Celis-Morales, C; Livingstone, Katherine M; Affleck, A; Navas-Carretero, S; San-Cristobal, R & Martinez, JA [Show all 27 contributors for this article] (2017). Correlates of overall and central obesity in adults from seven European countries: findings from the Food4Me Study. European Journal of Clinical Nutrition. ISSN 0954-3007. p. 1–13. doi: 10.1038/s41430-017-0004-y. Full text in Research Archive
• Strømmen, Kenneth; Haag, Alexander; Moltu, Sissel; Veierød, Marit Bragelien; Blakstad, Elin Wahl & Nakstad, Britt [Show all 12 contributors for this article] (2017). Enhanced nutrient supply to very low birth weight infants is associated with higher blood amino acid concentrations and improved growth. Clinical Nutrition ESPEN. ISSN 2405-4577. 18, p. 16–22. doi: 10.1016/j.clnesp.2017.01.003. Full text in Research Archive
• Øyen, Jannike; Gjesdal, Clara Gram; Karlsson, Therese; Svingen, Gard Frodahl Tveitevåg; Tell, Grethe S. & Strand, Elin [Show all 11 contributors for this article] (2017). Dietary choline intake is directly associated with bone mineral density in the Hordaland Health Study. Journal of Nutrition. ISSN 0022-3166. 147(4), p. 572–578. doi: 10.3945/jn.116.243006. Full text in Research Archive
• San-Cristobal, Rodrigo; Navas-Carretero, Santiago; Livingstone, Katherine M.; Celis-Morales, Carlos; Macready, Anna L. & Fallaize, Rosalind [Show all 26 contributors for this article] (2017). Mediterranean diet adherence and genetic background roles within a web-based nutritional intervention: The food4me study. Nutrients. 9:1107(10), p. 1–17. doi: 10.3390/nu9101107. Full text in Research Archive
• Livingstone, Katherine M.; Celis-Morales, Carlos; Macready, Anna L.; Fallaize, Rosalind; Forster, Hannah & Woolhead, Clara [Show all 27 contributors for this article] (2017). Characteristics of European adults who dropped out from the Food4Me Internet-based personalised nutrition intervention. Public Health Nutrition (PHN). ISSN 1368-9800. 20(1), p. 53–63. doi: 10.1017/S1368980016002020. Full text in Research Archive
• Pérez-Martínez, Pablo; Mikhailidis, Dimitri P.; Athyros, Vasilios G.; Bullo, Monica; Couture, Patrick & Covas, Maria I. [Show all 34 contributors for this article] (2017). Lifestyle recommendations for the prevention and management of metabolic syndrome: An international panel recommendation. Nutrition reviews. ISSN 0029-6643. 75(5), p. 307–326. doi: 10.1093/nutrit/nux014. Full text in Research Archive
• O´Donovan, CB; Walsh, MC; Woodhead, C; Forster, Hannah; Celis-Morales, Carlos & Fallaize, Rosalind [Show all 28 contributors for this article] (2017). Metabotyping for the development of tailored dietary advice solutions in a European population: the Food4Me study. British Journal of Nutrition. ISSN 0007-1145. 118(5), p. 561–569. doi: 10.1017/S0007114517002069. Full text in Research Archive
• Brouwer-Brolsma, EM; Brennan, L; Drevon, Christian A; Kranen, H van; Manach, C & Dragsted, LO [Show all 26 contributors for this article] (2017). Combining traditional dietary assessment methods with novel metabolomics techniques: Current efforts by the Food Biomarker Alliance. Proceedings of the Nutrition Society. ISSN 0029-6651. 76(4), p. 619–627. doi: 10.1017/S00029665117003949. Full text in Research Archive
• Karlsson, Therese; Rosendahl-Riise, Hanne; Dierkes, Jutta; Drevon, Christian A; Tell, Grethe S. & Nygård, Ottar (2017). Associations between fish intake and the metabolic syndrome and its components among middle-aged men and women: the Hordaland Health Study. Food & Nutrition Research (FNR). ISSN 1654-6628. 61(1). doi: 10.1080/16546628.2017.1347479. Full text in Research Archive Show summary

  In epidemiologic studies, the relationship between fish consumption and the metabolic syndrome (MetS) have been inconclusive and sex differences reported. The aim was to investigate associations between fish intake and the MetS in a cross-sectional study of men and women. Fish intake, waist circumference, triglycerides (TG), HDL-C, glucose and blood pressure were assessed among 2874 men and women (46–49 y) in the Hordaland Health Study (1997–1999). Fatty fish intake was inversely associated with TG in men only; mean difference in TG between highest and lowest quartile of fatty fish intake was –0.33 mmol/L (95% CI: –0.51, –0.15). Lean fish intake was inversely associated with TG in women only; mean difference in TG between highest and lowest quartile of lean fish intake was –0.23 mmol/L (95% CI: –0.34, –0.11). Fatty fish intake was positively associated with serum HDL-C in both men and women. Total fish intake was inversely associated with MetS; adjusted OR 0.75 (95% CI 0.57, 0.97). Higher fish intake was associated with lower odds of having MetS possibly driven by associations of higher fish intake with lower TG and higher HDL-C. The findings of differential associations by sex needs to be confirmed and possible biologic mechanisms explored.

• Pourteymour, Shirin; Hjorth, Marit; Lee-Ødegård, Sindre; Holen, Torgeir; Langleite, Torgrim Mikal & Jensen, Jørgen [Show all 9 contributors for this article] (2017). Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise. Physiological Reports. 5:e13459(19), p. 1–14. doi: 10.14814/phy2.13459. Full text in Research Archive Show summary

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

• Gjevestad, Gyrd Omholt; Hamarsland, Håvard; Raastad, Truls; Ottestad, Inger; Christensen, Jacob J. & Eckardt, Kristin [Show all 10 contributors for this article] (2017). Gene expression is differentially regulated in skeletal muscle and circulating immune cells in response to an acute bout of high-load strength exercise. Genes & Nutrition. ISSN 1555-8932. 12:8, p. 1–11. doi: 10.1186/s12263-017-0556-4. Full text in Research Archive Show summary

  Background: High-intensity exercise induces many metabolic responses. In is unknown whether the response in the peripheral blood mononuclear cells (PBMCs) reflects the response in skeletal muscle and whether mRNA expression after exercise can be modulated by nutritional intake. The aims were to (i) investigate the effect of dairy proteins on acute responses to exercise in skeletal muscle and PBMCs measuring gene expression and (ii) compare this response in young and older subjects. Methods: We performed two separate studies in young (20–40 years) and older subjects (≥70 years). Subjects were randomly allocated to a milk group or a whey group. Supplements were provided immediately after a standardized exercise session. We measured mRNA expression of selected genes after a standardized breakfast and 60/120 min after finishing the exercise, using RT-qPCR. Results: We observed no significant differences in mRNA expression between the milk and the whey group; thus, we merged both groups for further analysis. The mRNA expression of IL6, TNF, and CCL2 in skeletal muscle increased significantly after exercise compared with smaller or no increase, in mRNA expression in PBMCs in all participants. The mRNA expression of IL1RN, IL8, and IL10 increased significantly in skeletal muscle and PBMCs. Some mRNA transcripts were differently regulated in older compared to younger participants in PBMCs. Conclusions: An acute bout of heavy-load strength exercise, followed by protein supplementation, caused overlapping, but also unique, responses in skeletal muscle and PBMCs, suggesting tissue-specific functions in response to exercise. However, no different effects of the different protein supplements were observed. Altered mRNA expressions in PBMCs of older participants may affect regenerative mechanisms.

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• Retterstøl, Kjetil; Drevon, Christian A & Blomhoff, Rune (2019). Kapittel 28: Hjerte-karsykdommer. Cappelen Damm Akademisk. ISBN 9788202643904. 540 p. Full text in Research Archive

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• Lee-Ødegård, Sindre; Norheim, Frode Amador; Langleite, Torgrim Mikal; Gulseth, Hanne Løvdal; Birkeland, Kåre Inge & Drevon, Christian A (2022). Correction to: Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight (Diabetologia, (2019), 62, 6, (1048-1064), 10.1007/s00125-019-4866-5). Diabetologia. ISSN 0012-186X. doi: 10.1007/s00125-022-05841-z. Full text in Research Archive
• Strømmen, Kenneth; Lyche, Jan Ludvig; Moltu, Sissel; Müller, Mette Helen Bjørge; Blakstad, Elin Wahl & Almaas, Astrid Nylander [Show all 12 contributors for this article] (2021). Corrigendum to “High urinary concentrations of parabens and bisphenol A in very low birth weight infants”. Chemosphere. ISSN 0045-6535. 275. doi: 10.1016/j.chemosphere.2021.130613. Full text in Research Archive
• Livingstone, Katherine M.; Celis-Morales, Carlos; Lara, Jose; Woolhead, Clara; O'Donovan, Clare B. & Forster, Hannah [Show all 28 contributors for this article] (2019). Corrigendum: Clustering of adherence to personalised dietary recommendations and changes in healthy eating index within the Food4Me study (Public Health Nutrition 19:18 (3296-305) DOI: 10.1017/S1368980016001932). Public Health Nutrition (PHN). ISSN 1368-9800. 22(11), p. 2141–2146. doi: 10.1017/S1368980019001502. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode Amador; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Aker, Andreas Helge Mikael & Gundersen, Thomas Erik [Show all 9 contributors for this article] (2018). Author Correction: Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. Scientific Reports. 8(1), p. 7885–7885. doi: 10.1038/s41598-018-26061-9. Full text in Research Archive
• Henriksen, Christine; Almaas, Astrid; Westerberg, Ane Cecilie; Drevon, Christian A; Iversen, Per Ole & Nakstad, Britt (2017). Growth, metabolic profile and IQ in 8 years old children born preterm: Follow-up of an RCT with essential fatty acids (foredraget ble holdt på norsk). Full text in Research Archive

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