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Time-restricted feeding (TRF) improves metabolism independent of dietary macronutrient composition or energy restriction. To elucidate mechanisms underpinning the effects of short-term TRF, we investigated skeletal muscle and serum metabolic and transcriptomic profiles from 11 men with overweight/obesity after TRF (8 h day −1 ) and extended feeding (EXF, 15 h day −1 ) in a randomised cross-over design (trial registration: ACTRN12617000165381). Here we show that muscle core clock gene expression was similar after both interventions. TRF increases the amplitude of oscillating muscle transcripts, but not muscle or serum metabolites. In muscle, TRF induces rhythmicity of several amino acid transporter genes and metabolites. In serum, lipids are the largest class of periodic metabolites, while the majority of phase-shifted metabolites are amino acid related. In conclusion, short-term TRF in overweight men affects the rhythmicity of serum and muscle metabolites and regulates the rhythmicity of genes controlling amino acid transport, without perturbing core clock gene expression. Time restricted feeding has several health benefits. Here the authors perform a randomised cross-over study with 11 men with overweight/obesity to investigate how time restricted feeding affects skeletal muscle and serum, and report that it does not affect the core circadian machinery, but modifies periodicity in amino acid related metabolites and transporters.

High fat feeding impairs skeletal muscle metabolic flexibility and induces insulin resistance, whereas exercise training exerts positive effects on substrate handling and improves insulin sensitivity. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression and DNA methylation. HFD markedly induced expression of immune and inflammatory genes, which was not attenuated by Ex. Conversely, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed a significant association between DNA methylation and gene expression changes were PYGM, which was epigenetically regulated in both groups, and ANGPTL4, which was regulated only following Ex. In conclusion, while short-term Ex did not prevent a HFD-induced inflammatory response, it provoked a genomic response that may protect skeletal muscle from atrophy. These epigenetic adaptations provide mechanistic insight into the gene-specific regulation of inflammatory and metabolic processes in human skeletal muscle.

Dietary factors influence male reproductive function in both experimental and epidemiological studies. However, there are currently no specific dietary guidelines for male preconception health. Here, we use the Nutritional Geometry framework to examine the effects of dietary macronutrient balance on reproductive traits in C57BL/6 J male mice. Dietary effects are observed in a range of morphological, testicular and spermatozoa traits, although the relative influence of protein, fat, carbohydrate, and their interactions differ depending on the trait being examined. Interestingly, dietary fat has a positive influence on sperm motility and antioxidant capacity, differing to typical high fat diet studies where calorie content is not controlled for. Moreover, body adiposity is not significantly correlated with any of the reproductive traits measured in this study. These results demonstrate the importance of macronutrient balance and calorie intake on reproductive function and support the need to develop specific, targeted, preconception dietary guidelines for males. We know that nutrition and obesity can impact male fertility, but specific dietary guidelines for men trying to conceive don’t exist. Here the authors show that diet composition is likely more important than body fat in influencing reproductive traits and each macronutrient has different impacts.

Key Points Epigenetic processes have been implicated in the pathogenesis of type 2 diabetes mellitus Diet and exercise might affect the epigenome over several generations Epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors Regulation of gene expression by DNA methylation and histone modification occurs by a mechanism that impairs the access of transcriptional machinery to the promoters Studying the epigenetic signatures of insulin resistance and the adaptive response to exercise might provide insight into gene–environment networks that control glucose and energy homeostasis. In this Review, Romain Barrès and Juleen Zierath outline the current understanding of the mechanisms underlying how lifestyle factors affect epigenetic changes involved in the risk of type 2 diabetes mellitus. The latest findings on the mechanisms by which diet and exercise affect the epigenome are also discussed. Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell division. Epigenetic modifications can arise from a variety of environmental exposures including undernutrition, obesity, physical activity, stress and toxins. Transient epigenetic changes across the entire genome can influence metabolic outcomes and might or might not be heritable. These modifications direct and maintain the cell-type specific gene expression state. Transient epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors. A detailed understanding of the epigenetic signatures of insulin resistance and the adaptive response to exercise might identify new therapeutic targets that can be further developed to improve insulin sensitivity and prevent obesity. This Review focuses on the current understanding of mechanisms by which lifestyle factors affect the epigenetic landscape in type 2 diabetes mellitus and obesity. Evidence from the past few years about the potential mechanisms by which diet and exercise affect the epigenome over several generations is discussed.

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation. Overexpression of miR-19b-3p in human skeletal muscle cells increases insulin signaling, glucose uptake, and maximal oxygen consumption, recapitulating the adaptive response to aerobic exercise training. Overexpression of miR-19b-3p in mouse flexor digitorum brevis muscle enhances contraction-induced glucose uptake, indicating that miR-19b-3p exerts control on exercise training-induced adaptations in skeletal muscle. Potential targets of miR-19b-3p that are reduced after aerobic exercise training include KIF13A , MAPK6 , RNF11 , and VPS37A . Amongst these, RNF11 silencing potentiates glucose uptake in human skeletal muscle cells. Collectively, we identify miR-19b-3p as an aerobic exercise training-induced miRNA that regulates skeletal muscle glucose metabolism. Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.

Innate circadian rhythms are critical for optimal tissue-specific functions, including skeletal muscle, a major insulin-sensitive tissue responsible for glucose homeostasis. We determined whether transcriptional oscillations are associated with CpG methylation changes in skeletal muscle. We performed rhythmicity analysis on the transcriptome and CpG methylome of circadian synchronized myotubes. We identified several transcripts and CpG-sites displaying oscillatory behavior, which were enriched with Gene Ontology terms related to metabolism and development. Oscillating CpG methylation was associated with rhythmic expression of 31 transcripts. Although circadian oscillations may be regulated by rhythmic DNA methylation, strong rhythmic associations between transcriptome and CpG methylation were not identified. This resource constitutes a transcriptomic/epigenomic atlas of skeletal muscle and regulation of circadian rhythms.

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Replacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC) in control and hyperglycemic conditions. HRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium ((86)Rb(+)) uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM). DNA binding activity was determined by electrical mobility shift assay (EMSA). Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α(1)-subunit protein expression, accompanied with increase in (86)Rb(+) uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α(1)-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6), concomitant with Na,K-ATPase α(1)-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α(1)-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing. Despite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C-peptide-mediated signaling. Importantly, only physiological concentrations of C-peptide elicit this effect.

IntroductionThe global prevalence of people living with overweight has tripled since 1975 and more than 40% of Danish women enter pregnancy being overweight. With the increasing rates of obesity observed in children, adolescents and adults, there is an urgent need for preventive measures. Risk factors for childhood obesity include maternal overweight or obesity before conception and excessive weight gain during pregnancy. Interventions aimed at modifying maternal lifestyle during pregnancy have demonstrated minimal positive or no impact on the health of the children. The ‘healthy lifestyle before and during pregnancy to prevent childhood obesity — the PRE-STORK trial’ aims to provide insights into the effect of a lifestyle intervention initiated before conception and continued during pregnancy in women with overweight or obesity, on neonatal adiposity in their children.Methods and analysisIn this randomised, two-arm, parallel-group, controlled trial, we will include 360 women with overweight or obesity (aged 18–40; body mass index 25–44 kg/m2) and their partners. The women will be randomised to receive either standard of care or a lifestyle intervention focused on preconception body weight reduction, regular physical exercise, healthy diet and support from a mentor before and during pregnancy. The primary outcome is the difference in neonatal adiposity measured in their children at birth. Children conceived during the trial will constitute a birth cohort, monitoring the effects on their health until the age of 18 years.Ethics and disseminationThe trial has been approved by the Regional Committee on Health Research Ethics in the Capital Region of Denmark (identification number H-22011403) and will be conducted in agreement with the Declaration of Helsinki. All results, whether positive, negative and inconclusive, will be disseminated at national or international scientific meetings and in peer-reviewed scientific journals.Trial registration numberClinicalTrials.gov: NCT05578690 (October 2022).