Romain BARRES

Butyrate inhibits IL-1β-induced inflammatory gene expression by suppression of NF-κB activity in pancreatic beta cells

Publisher: Elsevier BV

Date: 09-2022

DOI: 10.1016/J.JBC.2022.102312

Cold-induction of afadin in brown fat supports its thermogenic capacity

Publisher: Springer Science and Business Media LLC

Date: 07-0005

DOI: 10.1038/S41598-021-89207-2

Abstract: The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β 3 -adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

Hepatocyte-specific perturbation of NAD+ biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.JBC.2021.101388

Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

Publisher: EMBO

Date: 02-07-2019

DOI: 10.15252/EMBR.201948216

Grandpaternal-induced transgenerational dietary reprogramming of the unfolded protein response in skeletal muscle

Publisher: Elsevier BV

Date: 07-2017

DOI: 10.1016/J.MOLMET.2017.05.009

Time trends in epigenetic signatures and population health risks

Publisher: Elsevier

Date: 2021

DOI: 10.1016/B978-0-12-820951-6.00006-5

Altered expression and insulin-induced trafficking of Na+-K +-ATPase in rat skeletal muscle: Effects of high-fat diet and exercise

Publisher: American Physiological Society

Date: 07-2009

DOI: 10.1152/AJPENDO.90990.2008

Abstract: Skeletal muscle Na + -K + -ATPase plays a central role in the clearance of K + from the extracellular fluid, therefore maintaining blood [K + ]. Na + -K + -ATPase activity in peripheral tissue is impaired in insulin resistant states. We determined effects of high-fat diet (HFD) and exercise training (ET) on skeletal muscle Na + -K + -ATPase subunit expression and insulin-stimulated translocation. Skeletal muscle expression of Na + -K + -ATPase isoforms and transcription factor DNA binding was determined before or after 5 days of swim training in Wistar rats fed chow or HFD for 4 or 12 wk. Skeletal muscle insulin resistance was observed after 12 wk of HFD. Na + -K + -ATPase α 1 -subunit protein expression was increased 1.6-fold ( P 0.05), whereas α 2 - and β 1 -subunits and protein expression were decreased twofold ( P 0.01) in parallel with decrease in plasma membrane Na + -K + -ATPase activity after 4 wk of HFD. Exercise training restored α 1 -, α 2 -, and β 1 -subunit expression and Na + -K + -ATPase activity to control levels and reduced β 2 -subunit expression 2.2-fold ( P 0.05). DNA binding activity of the α 1 -subunit-regulating transcription factor ZEB (AREB6) and α 1 mRNA expression were increased after HFD and restored by ET. DNA binding activity of Sp-1, a transcription factor involved in the regulation of α 2 - and β 1 -subunit expression, was decreased after HFD. ET increased phosphorylation of the Na + -K + -ATPase regulatory protein phospholemman. Phospholemman mRNA and protein expression were increased after HFD and restored to control levels after ET. Insulin-stimulated translocation of the α 2 -subunit to plasma membrane was impaired by HFD, whereas α 1 -subunit translocation remained unchanged. Alterations in sodium pump function precede the development of skeletal muscle insulin resistance. Disturbances in skeletal muscle Na + -K + -ATPase regulation, particularly the α 2 -subunit, may contribute to impaired ion homeostasis in insulin-resistant states such as obesity and type 2 diabetes.

Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ-free mice.

Publisher: Wiley

Date: 10-10-2018

DOI: 10.1096/FJ.201800787R

Contraction influences Per2 gene expression in skeletal muscle through a calcium‐dependent pathway

Publisher: Wiley

Date: 04-10-2020

DOI: 10.1113/JP280428

Abstract: Exercising at different times of day elicits different effects on exercise performance and metabolic health. However, the specific signals driving the observed time‐of‐day specific effects of exercise have not been fully identified. Exercise influences the skeletal muscle circadian clock, although the relative contribution of muscle contraction and extracellular signals is unknown. Here, we show that contraction acutely increases the expression of the core circadian clock gene Period Circadian Regulator 2 (Per2) and phase‐shifts Per2 rhythmicity in muscle cells. This contraction effect on core clock genes is mediated through a calcium‐dependant mechanism The results obtained in the present study suggest that a proportion of the ability of exercise to entrain the skeletal muscle clock is driven directly by muscle contraction. Contraction interventions may be used to mimic some time‐of‐day specific effects of exercise on metabolism and muscle performance. Exercise entrains the central and peripheral circadian clocks, although the mechanism by which exercise modulates expression of skeletal muscle clock genes is unclear. The present study aimed to determine whether skeletal muscle contraction alone could directly influence circadian rhythmicity and uncover the underlying mechanism by which contraction modulates clock gene expression. We investigated the expression of core clock genes in human skeletal muscle after acute exercise, as well as following in vitro contraction in mouse soleus muscle and cultured C2C12 skeletal muscle myotubes. Additionally, we interrogated the molecular pathways by which skeletal muscle contraction could influence clock gene expression. Contraction acutely increased the expression of the core circadian clock gene Period Circadian Regulator 2 (Per2) and phase‐shifted Per2 rhythmicity in C2C12 myotubes in vitro . Further investigation revealed that pharmacologically increasing cytosolic calcium concentrations by ionomycin treatment mimicked the effect of contraction on Per2 expression. Similarly, treatment with a calcium channel blocker, nifedipine, blocked the effect of electric pulse stimulation‐induced contraction on Per2 expression. Increased calcium influx from contraction lead to binding of the phosphorylated form of cAMP response element‐binding protein (CREB) to the Per2 promoter, suggesting a role of CREB in contraction‐induced Per2 transcription. Thus, by dissociating the effect of muscle contraction alone from the whole effect of exercise, our investigations indicate that a proportion of the ability of exercise to entrain the skeletal muscle clock is driven directly by contraction.

Paternal high‐fat diet transgenerationally impacts hepatic immunometabolism

Publisher: Wiley

Date: 15-02-2019

DOI: 10.1096/FJ.201801879RR

Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots

Publisher: Springer Science and Business Media LLC

Date: 25-01-2018

DOI: 10.1186/S13148-018-0446-7

Structured supervised exercise training or motivational counselling during pregnancy on physical activity level and health of mother and offspring: FitMum study protocol

Publisher: BMJ

Date: 03-2021

DOI: 10.1136/BMJOPEN-2020-043671

Abstract: A physically active lifestyle during pregnancy improves maternal and offspring health but can be difficult to follow. In Denmark, less than 40% of pregnant women meet physical activity (PA) recommendations. The FitMum study aims to explore strategies to increase PA during pregnancy among women with low PA and assess the health effects of PA. This paper presents the FitMum protocol, which evaluates the effects of structured supervised exercise training or motivational counselling supported by health technology during pregnancy on PA level and health of mother and offspring. A single-site three-arm randomised controlled trial that aims to recruit 220 healthy, pregnant women with gestational age (GA) no later than week 15 and whose PA level does not exceed one hour/week. Participants are randomised to one of three groups: structured supervised exercise training consisting of three weekly exercise sessions, motivational counselling supported by health technology or a control group receiving standard care. The interventions take place from randomisation until delivery. The primary outcome is min/week of moderate-to-vigorous intensity PA (MVPA) as determined by a commercial activity tracker, collected from randomisation until GA of 28 weeks and 0-6 days, and the secondary outcome is gestational weight gain (GWG). Additional outcomes are complementary measures of PA clinical and psychological health parameters in participant, partner and offspring analyses of blood, placenta and breastmilk s les process evaluation of interventions and personal understandings of PA. The study is approved by the Danish National Committee on Health Research Ethics (# H-18011067) and the Danish Data Protection Agency (# P-2019-512). Findings will be disseminated via peer-reviewed publications, at conferences, and to health professionals via science theatre performances. NCT03679130 . This paper was written per the study protocol version 8 dated 28 August 2019.

Impact of dietary macronutrient composition on gene regulation in adipose tissue

Publisher: Research Square Platform LLC

Date: 04-08-2023

DOI: 10.21203/RS.3.RS-2973236/V1

Abstract: Diet is a key lifestyle component that influences metabolic health through several factors, including total energy intake and macronutrient composition. While the impact of caloric intake on gene expression and physiological phenomenon in various tissues is well described, the influence of dietary macronutrient composition on these parameters is less well studied. Here, we used the Nutritional Geometry framework to investigate the role of macronutrient composition on metabolic function and gene regulation in adipose tissue. Using ten isocaloric diets that vary systematically in their proportion of energy from fat, protein, and carbohydrates, we found that gene expression and splicing are highly responsive to macronutrient composition, with distinct sets of genes regulated by different macronutrient interactions. Specifically, the expression of many genes associated with Bardet-Biedl syndrome was responsive to dietary fat content. Splicing and expression changes occurred in largely separate gene sets, highlighting distinct mechanisms by which dietary composition influences the transcriptome and emphasizing the importance of considering splicing changes to more fully capture the gene regulation response to environmental changes such as diet. Our study provides insight into the gene regulation plasticity of adipose tissue in response to macronutrient composition, beyond the already well-characterized response to caloric intake.

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.MOLMET.2022.101440

Exercise during pregnancy mitigates negative effects of parental obesity on metabolic function in adult mouse offspring

Publisher: American Physiological Society

Date: 03-2021

DOI: 10.1152/JAPPLPHYSIOL.00641.2020

Abstract: Maternal or paternal obesity causes metabolic impairment in adult offspring in mice. Maternal exercise during gestation can completely mitigate metabolic impairment. Maternal obesity, but not paternal obesity, results in hypermethylation of the Pgc-1α promoter at CpG-260, which can be abolished by maternal exercise.

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

Publisher: Hindawi Limited

Date: 2016

DOI: 10.1155/2016/8539057

Abstract: Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.

Author Correction: Time-restricted feeding alters lipid and amino acid metabolite rhythmicity without perturbing clock gene expression

Publisher: Springer Science and Business Media LLC

Date: 08-10-2020

DOI: 10.1038/S41467-020-19100-5

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-cell bisulfite sequencing of spermatozoa from lean and obese humans reveals potential for the transmission of epimutations

Publisher: Cold Spring Harbor Laboratory

Date: 10-07-2021

DOI: 10.1101/2021.07.09.451752

Abstract: Epigenetic marks in gametes modulate developmental programming after fertilization. Spermatozoa from obese men exhibit distinct epigenetic signatures compared to lean men, however, whether epigenetic differences are concentrated in a sub-population of spermatozoa or spread across the ejaculate population is unknown. Here, by using whole-genome single-cell bisulfite sequencing on 87 motile spermatozoa from 8 in iduals (4 lean and 4 obese), we found that spermatozoa within single ejaculates are highly heterogeneous and contain subsets of spermatozoa with marked imprinting defects. Comparing lean and obese subjects, we discovered methylation differences across two large CpG dense regions located near PPM1D and LINC01237 . These findings confirm that sperm DNA methylation is altered in human obesity and indicate that single ejaculates contain subpopulations of spermatozoa carrying distinct DNA methylation patterns. Distinct epigenetic patterns of spermatozoa within an ejaculate may result in different intergenerational effects and therefore influence strategies aiming to prevent epigenetic-related disorders in the offspring.

The interaction between the adaptor protein APS and Enigma is involved in actin organisation

Publisher: Elsevier BV

Date: 08-2005

DOI: 10.1016/J.YEXCR.2005.05.008

Abstract: APS (adaptor protein with PH and SH2 domains) is an adaptor protein phosphorylated by several tyrosine kinase receptors including the insulin receptor. To identify novel binding partners of APS, we performed yeast two-hybrid screening. We identified Enigma, a PDZ and LIM domain-containing protein that was previously shown to be associated with the actin cytoskeleton. In HEK 293 cells, Enigma interacted specifically with APS, but not with the APS-related protein SH2-B. This interaction required the NPTY motif of APS and the LIM domains of Enigma. In NIH-3T3 cells that express the insulin receptor, Enigma and APS were partially co-localised with F-actin in small ruffling structures. Insulin increased the complex formation between APS and Enigma and their co-localisation in large F-actin containing ruffles. While in NIH-3T3 and HeLa cells the co-expression of both Enigma and APS did not modify the actin cytoskeleton organisation, expression of Enigma alone led to the formation of F-actin clusters. Similar alteration in actin cytoskeleton organisation was observed in cells expressing both Enigma and APS with a mutation in the NPTY motif. These results identify Enigma as a novel APS-binding protein and suggest that the APS/Enigma complex plays a critical role in actin cytoskeleton organisation.

Physical Activity and Insulin Sensitivity Independently Attenuate the Effect of FTO rs9939609 on Obesity

Publisher: American Diabetes Association

Date: 21-02-2023

DOI: 10.2337/DC22-2078

Abstract: The association between FTO rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, to assess whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms. Genetic association analyses comprised up to 19,585 in iduals. PA was self-reported, and IS was defined based on inverted HOMA insulin resistance index. Functional analyses were performed in muscle biopsies from 140 men and in cultured muscle cells. The BMI-increasing effect of the FTO rs9939609 A allele was attenuated by 47% with high PA (β [SE], −0.32 [0.10] kg/m2, P = 0.0013) and by 51% with high IS (−0.31 [0.09] kg/m2, P = 0.00028). Interestingly, these interactions were essentially independent (PA, −0.20 [0.09] kg/m2, P = 0.023 IS, −0.28 [0.09] kg/m2, P = 0.0011). The rs9939609 A allele was also associated with higher all-cause mortality and certain cardiometabolic outcomes (hazard ratio, 1.07–1.20, P & 0.04), and these effects tended to be weakened by greater PA and IS. Moreover, the rs9939609 A allele was associated with higher expression of FTO in skeletal muscle tissue (0.03 [0.01], P = 0.011), and in skeletal muscle cells, we identified a physical interaction between the FTO promoter and an enhancer region encompassing rs9939609. Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of FTO in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract FTO-related genetic predisposition to obesity.

Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism

Publisher: Springer Science and Business Media LLC

Date: 12-10-2021

DOI: 10.1038/S41467-021-26095-0

Abstract: 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.

Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action

Publisher: Wiley

Date: 21-06-2021

DOI: 10.1096/FJ.202100215R

Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1016/J.CELREP.2013.03.018

Abstract: DNA methylation provides a mechanism by which environmental factors can control insulin sensitivity in obesity. Here, we assessed DNA methylation in skeletal muscle from obese people before and after Roux-en-Y gastric bypass (RYGB). Obesity was associated with altered expression of a subset of genes enriched in metabolic process and mitochondrial function. After weight loss, the expression of the majority of the identified genes was normalized to levels observed in normal-weight, healthy controls. Among the 14 metabolic genes analyzed, promoter methylation of 11 genes was normalized to levels observed in the normal-weight, healthy subjects. Using bisulfite sequencing, we show that promoter methylation of PGC-1α and PDK4 is altered with obesity and restored to nonobese levels after RYGB-induced weight loss. A genome-wide DNA methylation analysis of skeletal muscle revealed that obesity is associated with hypermethylation at CpG shores and exonic regions close to transcription start sites. Our results provide evidence that obesity and RYGB-induced weight loss have a dynamic effect on the epigenome.

Endurance Training in Humans Modulates the Bacterial DNA Signature of Skeletal Muscle

Publisher: MDPI AG

Date: 29-12-2022

DOI: 10.3390/BIOMEDICINES10010064

Abstract: Accumulating evidence supports the existence of a tissue microbiota, which may regulate the physiological function of tissues in normal and pathological states. To gain insight into the regulation of tissue-borne bacteria in physiological conditions, we quantified and sequenced the 16S rRNA gene in aseptically collected skeletal muscle and blood s les from eight healthy male in iduals subjected to six weeks of endurance training. Potential contamination bias was evaluated and the taxa profiles of each tissue were established. We detected bacterial DNA in skeletal muscle and blood, with background noise levels of detected bacterial DNA considerably lower in control versus tissue s les. In both muscle and blood, Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes were the most prominent phyla. Endurance training changed the content of resident bacterial DNA in skeletal muscle but not in blood, with Pseudomonas being less abundant, and both Staphylococcus and Acinetobacter being more abundant in muscle after exercise. Our results provide evidence that endurance training specifically remodels the bacterial DNA profile of skeletal muscle in healthy young men. Future investigations may shed light on the physiological impact, if any, of training-induced changes in bacterial DNA in skeletal muscle.

The role of diet and exercise in the transgenerational epigenetic landscape of T2DM

Publisher: Springer Science and Business Media LLC

Date: 17-06-2016

DOI: 10.1038/NRENDO.2016.87

Abstract: Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell ision. 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.

Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

Publisher: Cold Spring Harbor Laboratory

Date: 25-02-2021

DOI: 10.1101/2021.02.24.432683

Abstract: Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes ARNTL, CLOCK , CRY1 and NR1D1 was altered in skeletal muscle from in iduals with T2D and this was coupled with reduced number and litude of cycling genes and disturbed circadian oxygen consumption. Mitochondrial associated genes were enriched for differential circadian litudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.

Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism

Publisher: Springer Science and Business Media LLC

Date: 06-2020

DOI: 10.1038/S41467-020-16537-6

Abstract: Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.

Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.MOLMET.2021.101271

GREM1 is epigenetically reprogrammed in muscle cells after exercise training and controls myogenesis and metabolism

Publisher: Cold Spring Harbor Laboratory

Date: 20-02-2020

DOI: 10.1101/2020.02.20.956300

Abstract: Exercise training improves skeletal muscle function, notably through tissue regeneration by muscle stem cells. Here, we hypothesized that exercise training reprograms the epigenome of muscle cell, which could account for better muscle function. Genome-wide DNA methylation of myotube cultures established from middle-aged obese men before and after endurance exercise training identified a differentially methylated region (DMR) located downstream of Gremlin 1 ( GREM1 ), which was associated with increased GREM1 expression. GREM1 expression was lower in muscle satellite cells from obese, compared to lean mice, and exercise training restored GREM1 levels to those of control animals. We show that GREM1 regulates muscle differentiation through the negative control of satellite cell self-renewal, and that GREM1 controls muscle lineage commitment and lipid oxidation through the AMPK pathway. Our study identifies novel functions of GREM1 and reveals an epigenetic mechanism by which exercise training reprograms muscle stem cells to improve skeletal muscle function.

Science AMA Series: We’re researchers at the NNF Center for Basic Metabolic Research, University of Copenhagen. We recently published a study showing that obesity may be inherited through epigenetic modifications in sperm. Ask us anything!

Publisher: No publisher found

Date: 2015

DOI: 10.15200/WINN.145009.95401

Abstracts of 51st EASD Annual Meeting

Publisher: Springer Science and Business Media LLC

Date: 12-08-2015

DOI: 10.1007/S00125-015-3687-4

Transforming growth factor β1 impairs the transcriptomic response to contraction in myotubes from women with polycystic ovary syndrome

Publisher: Wiley

Date: 27-06-2022

DOI: 10.1113/JP282954

Abstract: Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive‐aged women. Exercise is recommended as a first‐line therapy for women with PCOS to improve their overall health however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction. Following EPS, 4719 genes were differentially expressed (false discovery rate .05) in myotubes from women with PCOS compared to 173 in healthy women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factor β (TGFβ) ligands that are elevated in plasma of women with PCOS, TGFβ1 and anti‐Müllerian hormone (AMH), alone and on the EPS‐induced response. While AMH (30 ng/ml) had no effect, TGFβ1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise‐like transcriptional signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament. Our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, circulating factors like TGFβ1 may be responsible for the impaired adaptation to exercise in women with PCOS. image Gene expression responses to in vitro contraction (electrical pulse stimulation, EPS) are altered in myotubes from women with polycystic ovary syndrome (PCOS) compared to healthy controls, with an increased expression of genes related to pro‐inflammatory pathways. Transforming growth factor β1 (TGFβ1) upregulates genes related to extracellular matrix remodelling and reduces the expression of contractile genes in myotubes, regardless of the donor's health status. TGFβ1 alters the gene expression response to EPS, providing a possible mechanism for the impaired exercise adaptations in women with PCOS.

Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding

Publisher: Springer Science and Business Media LLC

Date: 05-07-2023

DOI: 10.1038/S41419-023-05906-W

Abstract: Insufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from in iduals with diabetes and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4 , Hes-1 , and Hey-1 which are transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism by which BMP-2 induces beta cell dysfunction and loss of cell maturity. Mouse islets exposed to BMP-2 for 10 days showed impaired glucose-stimulated insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of cell maturity and proliferation markers specific to the beta cell such as Ins1 , Ucn3 , and Ki67 and increased expression of Id1-4 , Hes-1 , and Hey-1 . The top 30 most regulated proteins significantly correlated with corresponding mRNA expression. BMP-2-induced gene expression changes were associated with a predominant reduction in acetylation of H3K27 and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2 induces loss of beta cell maturity and suggest that remodeling of H3K27ac and decreased NeuroD1 DNA binding activity participate in the effect of BMP-2 on beta cell dysfunction.

Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial

Publisher: Oxford University Press (OUP)

Date: 17-05-2022

DOI: 10.1093/HUMREP/DEAC096

Abstract: Does diet-induced weight loss improve semen parameters, and are these possible improvements maintained with sustained weight loss? An 8-week low-calorie diet-induced weight loss was associated with improved sperm concentration and sperm count, which were maintained after 1 year in men who maintained weight loss. Obesity is associated with impaired semen quality. Weight loss improves metabolic health in obesity, but there is a lack of knowledge on the acute and long-term effects of weight loss on semen parameters. This is a substudy of men with obesity enrolled in a randomized, controlled, double-blinded trial (the S-LITE trial). The trial was conducted between August 2016 and November 2019. A total of 56 men were included in the study and assigned to an initial 8-week low-calorie diet (800 kcal/day) followed by randomization to 52 weeks of either: placebo and habitual activity (placebo), exercise training and placebo (exercise), the Glucagon Like Peptide 1 (GLP-1) analogue liraglutide and habitual activity (liraglutide) or liraglutide in combination with exercise training (combination). Inclusion criteria were men who delivered semen s les, 18 to 65 years of age, and a body mass index between 32 and 43 kg/m2, but otherwise healthy. The study was carried out at Hvidovre Hospital and at the University of Copenhagen, and the participants were from the Greater Copenhagen Area. We assessed semen parameters and anthropometrics and collected blood s les before (T0), after the 8-week low-calorie dietary intervention (T1), and after 52 weeks (T2). The men lost on average 16.5 kg (95% CI: 15.2–17.8) body weight during the low-calorie diet, which increased sperm concentration 1.49-fold (95% CI: 1.18–1.88, P & 0.01) and sperm count 1.41-fold (95% CI: 1.07–1.87, P & 0.01). These improvements were maintained for 52 weeks in men who maintained the weight loss, but not in men who regained weight. Semen volume, sperm motility and motile sperm count did not change. The S-LITE trial was a randomized controlled trial of weight loss maintenance. Analysis of semen was preregistered to explore the effects of weight loss and weight loss maintenance on semen parameters, but definite inferences cannot be made. This study shows that sperm concentration and sperm count were improved after a diet-induced weight loss in men with obesity. Our findings indicate that either or both liraglutide and exercise as weight maintenance strategies may be used to maintain the improvements in sperm concentration and count. This work is supported by an excellence grant from the Novo Nordisk Foundation (NNF16OC0019968), a Challenge Programme Grant from the Novo Nordisk Foundation (NNF18OC0033754) and a grant from Helsefonden. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). Saxenda (liraglutide) and placebo pens were provided by Novo Nordisk. Cambridge Weight Plan diet products for the 8-week low-calorie diet were provided by Cambridge Weight Plan. E.A.: shareholder, employee of ExSeed Health Ltd. Grant Recipient from ExSeed Health Ltd and listed on Patents planned, issued or pending with ExSeed Health Ltd J.J.H.: consultant for Eli Lilly A/S and Novo Nordisk A/S. Lecture fees for Novo Nordisk A/S. Listed on Patents planned, issued or pending with the University of Copenhagen, Advocacy group for Antag Therapeutics and Bainan Biotech S.M.: lecture fees for Novo Nordisk A/S. Recipient of Support for attending meetings from Novo Nordisk A/S. Advisory boards of Novo Nordisk A/S Sanofi Aventis and Merck Sharp & Dohme. S.S.T.: research grant recipient Novo Nordisk. The remaining authors have no conflicts of interest to declare. The trial was approved by the Ethical Committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT Number: 2015-005585-32). ClinicalTrials.gov identifier (NCT number): NCT04122716. 11 May 2016. August 2016.

Research Highlights: Nutritional status affects the epigenomic profile of peripheral blood cells

Publisher: Future Medicine Ltd

Date: 06-2011

DOI: 10.2217/EPI.11.24

Abstract: Evaluation of: Wang X, Zhu H, Snieder H et al.: Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med. 8, 87 (2010) Milagro FI, C ión J, Cordero P et al.: A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss. FASEB J. 25(4), 1378–1389 (2011).

Insulin-induced serine 22 phosphorylation of retinoid X receptor alpha is dispensable for adipogenesis in brown adipocytes

Publisher: Informa UK Limited

Date: 2020

DOI: 10.1080/21623945.2020.1747352

Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Publisher: American Association for the Advancement of Science (AAAS)

Date: 22-10-2021

DOI: 10.1126/SCIADV.ABI9654

Abstract: Disturbances in daily rhythms of mitochondrial activity may contribute to skeletal muscle insulin resistance in type 2 diabetes.

Transcriptomic and epigenomics atlas of myotubes reveals insight into the circadian control of metabolism and development

Publisher: Future Medicine Ltd

Date: 04-2020

DOI: 10.2217/EPI-2019-0391

Abstract: Aim: 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. Materials & methods: We performed rhythmicity analysis on the transcriptome and CpG methylome of circadian synchronized myotubes. Results: 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. Conclusion: 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.

White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment

Publisher: Elsevier BV

Date: 02-2021

DOI: 10.1016/J.MOLMET.2020.101137

The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging

Publisher: American Association for the Advancement of Science (AAAS)

Date: 08-12-2021

DOI: 10.1126/SCITRANSLMED.ABC7367

Abstract: Exercise activates the lncRNA Cytor , which reestablishes fast-twitch muscle fibers in aged skeletal muscle, improving morphology and function.

Comparative analysis of sperm DNA methylation supports evolutionary acquired epigenetic plasticity for organ speciation

Publisher: Future Medicine Ltd

Date: 11-2022

DOI: 10.2217/EPI-2022-0168

Abstract: Aim: To perform a comparative epigenomic analysis of DNA methylation in spermatozoa from humans, mice, rats and mini-pigs. Materials & methods: Genome-wide DNA methylation analysis was used to compare the methylation profiles of orthologous CpG sites. Transcription profiles of early embryo development were analyzed to provide insight into the association between sperm methylation and gene expression programming. Results: We identified DNA methylation variation near genes related to the central nervous system and signal transduction. Gene expression dynamics at different time points of preimplantation stages were modestly associated with spermatozoal DNA methylation at the nearest promoters. Conclusion: Conserved genomic regions subject to epigenetic variation across different species were associated with specific organ functions, suggesting their potential contribution to organ speciation and long-term adaptation to the environment.

Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

Publisher: Life Science Alliance, LLC

Date: 27-10-2022

DOI: 10.26508/LSA.202201598

Abstract: Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.

Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function

Publisher: Springer Science and Business Media LLC

Date: 20-02-2018

DOI: 10.1038/S41366-018-0031-3

Abstract: Deterioration of the adipogenic potential of preadipocytes may contribute to adipose tissue dysfunction in obesity and type 2 diabetes (T2D). Here, we hypothesized that extracellular factors in obesity epigenetically reprogram adipogenesis potential and metabolic function of preadipocytes. The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitro differentiation using RNA sequencing. Reduced Representation Bisulfite Sequencing was used to establish the genome-wide DNA methylation profile of human preadipocytes and 3T3-L1 preadipocytes treated by the inflammatory cytokine Tumour Necrosis Factor-α (TNF-α) or palmitate. While preadipocytes from all obese subjects (Obese+Obese T2D), compared to those of Lean, were transcriptionally different in response to differentiation in culture, preadipocytes from Obese T2D showed impaired insulin signalling and a further transcriptomic shift towards altered adipocyte function. Cultures with a lower expression magnitude of adipogenic genes throughout differentiation (PLIN1, CIDEC, FABP4, ADIPOQ, LPL, PDK4, APOE, LIPE, FABP3, LEP, RBP4 and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocytes with TNF-α or palmitate markedly altered insulin responsiveness and metabolic function in the differentiated adipocytes, and remodelled DNA methylation and gene expression at specific genes, notably related to PPAR signalling. Our findings that preadipocytes retain the memory of the donor in culture and can be reprogrammed by extracellular factors support a mechanism by which adipocyte precursors are epigenetically reprogrammed in vivo. Epigenetic reprogramming of preadipocytes represents a mechanism by which metabolic function of visceral adipose tissue may be affected in the long term by past exposure to obesity- or T2D-specific factors.

Splicing across adipocyte differentiation is highly dynamic and impacted by metabolic phenotype

Publisher: Research Square Platform LLC

Date: 31-10-2023

DOI: 10.21203/RS.3.RS-3487148/V1

Author Correction: Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans

Publisher: Springer Science and Business Media LLC

Date: 19-03-2018

DOI: 10.1038/S41598-018-23227-3

Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

The Emerging Role of Epigenetics in Inflammation and Immunometabolism

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.TEM.2016.06.008

Abstract: Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications.

Dynamic epigenetic responses to muscle contraction

Publisher: Elsevier BV

Date: 07-2014

DOI: 10.1016/J.DRUDIS.2014.03.003

Abstract: Skeletal muscle is a malleable organ that responds to a single acute exercise bout by inducing the expression of genes involved in structural, metabolic and functional adaptations. Several epigenetic mechanisms including histone H4 deacetylation and loss of promoter methylation have been implicated in modifying exercise-responsive gene expression. These transient changes suggest that epigenetic mechanisms are not restricted to early stages of human development but are broad dynamic controllers of genomic plasticity in response to environmental factors.

DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy—A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring

Publisher: MDPI AG

Date: 26-05-2022

DOI: 10.3390/BIOMEDICINES10061244

Abstract: Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring’s own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring’s own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies.

Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1016/J.CMET.2019.03.013

Abstract: While the timing of food intake is important, it is unclear whether the effects of exercise on energy metabolism are restricted to unique time windows. As circadian regulation is key to controlling metabolism, understanding the impact of exercise performed at different times of the day is relevant for physiology and homeostasis. Using high-throughput transcriptomic and metabolomic approaches, we identify distinct responses of metabolic oscillations that characterize exercise in either the early rest phase or the early active phase in mice. Notably, glycolytic activation is specific to exercise at the active phase. At the molecular level, HIF1α, a central regulator of glycolysis during hypoxia, is selectively activated in a time-dependent manner upon exercise, resulting in carbohydrate exhaustion, usage of alternative energy sources, and adaptation of systemic energy expenditure. Our findings demonstrate that the time of day is a critical factor to lify the beneficial impact of exercise on both metabolic pathways within skeletal muscle and systemic energy homeostasis.

ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth

Publisher: Public Library of Science (PLoS)

Date: 15-12-2009

DOI: 10.1371/JOURNAL.PBIO.1000256

In Situ Fixation Redefines Quiescence and Early Activation of Skeletal Muscle Stem Cells

Publisher: Elsevier BV

Date: 11-2017

DOI: 10.1016/J.CELREP.2017.10.080

Abstract: State of the art techniques have been developed to isolate and analyze cells from various tissues, aiming to capture their in vivo state. However, the majority of cell isolation protocols involve lengthy mechanical and enzymatic dissociation steps followed by flow cytometry, exposing cells to stress and disrupting their physiological niche. Focusing on adult skeletal muscle stem cells, we have developed a protocol that circumvents the impact of isolation procedures and captures cells in their native quiescent state. We show that current isolation protocols induce major transcriptional changes accompanied by specific histone modifications while having negligible effects on DNA methylation. In addition to proposing a protocol to avoid isolation-induced artifacts, our study reveals previously undetected quiescence and early activation genes of potential biological interest.

Strenuous physical exercise adversely affects monocyte chemotaxis

Publisher: Georg Thieme Verlag KG

Date: 2011

DOI: 10.1160/TH10-06-0363

Abstract: Physical exercise is important for proper cardiovascular function and disease prevention, but it may influence the immune system. We evaluated the effect of strenuous exercise on monocyte chemotaxis. Monocytes were isolated from blood of 13 young, healthy, sedentary in iduals participating in a three-week training program which consisted of repeated exercise bouts. Monocyte chemotaxis and serological biomarkers were investigated at baseline, after three weeks training and after four weeks recovery. Chemotaxis towards vascular endothelial growth factor-A (VEGF-A) and transforming growth factor-β1 (TGF-β1) was completely inhibited immediately after training (p .01), and remained so after four weeks recovery. Likewise, monocyte chemoattractant protein-1 (MCP-1)-induced migration declined after training (p .01) and improved only partially during the recovery period. MCP-1 serum levels were significantly reduced after four weeks recovery compared to baseline (p .01). Total blood antioxidant capacity was enhanced at this time point (p .01). Monocyte chemokinesis, TGF-β1 and nitric oxide serum levels remained unchanged during the study. Strenuous three-week training consisting of repeated exercise bouts in healthy, sedentary in iduals reduces monocyte chemotaxis. It remains to be established, whether this is a sound adaptation to increased stimuli or an untoward reaction to overtraining. Nevertheless, the effect remains for several weeks with no exercise.

Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes

Publisher: Springer Science and Business Media LLC

Date: 19-11-2021

DOI: 10.1038/S41366-021-01021-Y

Abstract: In obesity, adipose tissue dysfunction resulting from excessive fat accumulation leads to systemic insulin resistance (IR), the underlying alteration of Type 2 Diabetes. The specific pathways dysregulated in dysfunctional adipocytes and the extent to which it affects adipose metabolic functions remain incompletely characterized. We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceral white adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulin sensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming and glucose utilization using We found that gene expression associated with impaired glucose and lipid metabolism and inflammation represented the strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in mature human white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functions such as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucose metabolism, with higher incorporation of glucose into citrate, but not into downstream metabolites within the TCA cycle. Collectively, our data highlight the importance of obesity-derived insulin resistance in impacting the expression of key metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation in adipose dysfunction in humans.

Ionizing Radiation Potentiates High-Fat Diet–Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells

Publisher: American Diabetes Association

Date: 20-09-2016

DOI: 10.2337/DB16-0364

Abstract: Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes later in life. We hypothesized that irradiation reprograms the epigenome of metabolic progenitor cells, which could account for impaired metabolism after cancer treatment. C57Bl/6 mice were treated with a single dose of irradiation and subjected to high-fat diet (HFD). RNA sequencing and reduced representation bisulfite sequencing were used to create transcriptomic and epigenomic profiles of preadipocytes and skeletal muscle satellite cells collected from irradiated mice. Mice subjected to total body irradiation showed alterations in glucose metabolism and, when challenged with HFD, marked hyperinsulinemia. Insulin signaling was chronically disrupted in skeletal muscle and adipose progenitor cells collected from irradiated mice and differentiated in culture. Epigenomic profiling of skeletal muscle and adipose progenitor cells from irradiated animals revealed substantial DNA methylation changes, notably for genes regulating the cell cycle, glucose/lipid metabolism, and expression of epigenetic modifiers. Our results show that total body irradiation alters intracellular signaling and epigenetic pathways regulating cell proliferation and differentiation of skeletal muscle and adipose progenitor cells and provide a possible mechanism by which irradiation used in cancer treatment increases the risk for metabolic disease later in life.

Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.CMET.2012.01.001

Abstract: DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1α, PDK4, and PPAR-δ, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1α, PDK4, and PPAR-δ was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation.

Chronic high-fat diet in fathers programs ß-cell dysfunction in female rat offspring

Publisher: Springer Science and Business Media LLC

Date: 10-2010

DOI: 10.1038/NATURE09491

Abstract: The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01) genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.

Role of Adenosine 5′-Monophosphate-Activated Protein Kinase in Interleukin-6 Release from Isolated Mouse Skeletal Muscle

Publisher: The Endocrine Society

Date: 02-2009

DOI: 10.1210/EN.2008-1204

Abstract: IL-6 is released from skeletal muscle during exercise and has consequently been implicated to mediate beneficial effects on whole-body metabolism. Using 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), a pharmacological activator of 5′-AMP-activated protein kinase (AMPK), we tested the hypothesis that AMPK modulates IL-6 release from isolated muscle. Skeletal muscle from AMPKα2 kinase-dead transgenic, AMPKα1 knockout (KO) and AMPKγ3 KO mice and respective wild-type littermates was incubated in vitro, in the absence or presence of 2 mmol/liter AICAR. Skeletal muscle from wild-type mice was also incubated with the AMPK activator A-769662. Incubation of mouse glycolytic extensor digitorum longus and oxidative soleus muscle for 2 h was associated with profound IL-6 mRNA production and protein release, which was suppressed by AICAR (P & 0.001). Basal IL-6 release from soleus was increased between AMPKα2 kinase-dead and AMPKα1 KO and their respective wild-type littermates (P & 0.05), suggesting AMPK participates in the regulation of IL-6 release from oxidative muscle. The effect of AICAR on muscle IL-6 release was similar between AMPKα2 KD, AMPKα1 KO, and AMPKγ3 KO mice and their respective wild-type littermates (P & 0.001), indicating AICAR-mediated suppression of IL-6 mRNA expression and protein release is independent of AMPK function. However, IL-6 release from soleus, but not extensor digitorum longus, was reduced 45% by A-769662. Our results on basal and A-769662-mediated IL-6 release provide evidence for a role of AMPK in the regulation of IL-6 release from oxidative skeletal muscle. Furthermore, in addition to activating AMPK, AICAR suppresses IL-6 release by an unknown, AMPK-independent mechanism. Using transgenic and knockout mouse models to perturb AMP-activated protein kinase (AMPK) signaling, we provide evidence that AMPK-dependent pathways regulate IL-6 release from isolated oxidative skeletal muscle.

NAMPT-dependent NAD ⁺ biosynthesis controls circadian metabolism in a tissue-specific manner

Publisher: Proceedings of the National Academy of Sciences

Date: 30-03-2023

DOI: 10.1073/PNAS.2220102120

Abstract: Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD + , which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD + levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the litude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD + biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD + abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD + synthesis.

Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.CELL.2014.07.051

Abstract: Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

DNA methylation in metabolic disorders

Publisher: Elsevier BV

Date: 04-2011

DOI: 10.3945/AJCN.110.001933

Abstract: DNA methylation is a major epigenetic modification that controls gene expression in physiologic and pathologic states. Metabolic diseases such as diabetes and obesity are associated with profound alterations in gene expression that are caused by genetic and environmental factors. Recent reports have provided evidence that environmental factors at all ages could modify DNA methylation in somatic tissues, which suggests that DNA methylation is a more dynamic process than previously appreciated. Because of the importance of lifestyle factors in metabolic disorders, DNA methylation provides a mechanism by which environmental factors, including diet and exercise, can modify genetic predisposition to disease. This article considers the current evidence that defines a role for DNA methylation in metabolic disorders.

Evidence Suggesting Absence of Mitochondrial DNA Methylation

Publisher: Frontiers Media SA

Date: 11-2017

DOI: 10.3389/FGENE.2017.00166

Muscle Contraction Induces Acute Hydroxymethylation of the Exercise-Responsive Gene Nr4a3

Publisher: Frontiers Media SA

Date: 23-12-2016

DOI: 10.3389/FENDO.2016.00165

MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives

Publisher: Elsevier BV

Date: 11-2022

DOI: 10.1016/J.MOLMET.2022.101581

Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans

Publisher: Springer Science and Business Media LLC

Date: 05-11-2022

DOI: 10.1038/S41598-022-21938-2

Abstract: The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18 F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (− 8.4%, P = 0.032 vs 15.7%, P 0.0005) and S1P (− 41.0%, P 0.0005 vs 19.1%, P 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the in idual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (β: 0.44, 95% CI [0.06–0.81], P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI [− 0.01–0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.

Seasonal light hours modulate peripheral clocks and energy metabolism in mice

Publisher: Elsevier BV

Date: 10-2023

DOI: 10.1016/J.CMET.2023.08.005

Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans

Publisher: Springer Science and Business Media LLC

Date: 09-11-2017

DOI: 10.1038/S41598-017-15420-7

Abstract: 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.

Non-CpG Methylation of the PGC-1α Promoter through DNMT3B Controls Mitochondrial Density

Publisher: Elsevier BV

Date: 09-2009

DOI: 10.1016/J.CMET.2009.07.011

Abstract: Epigenetic modification through DNA methylation is implicated in metabolic disease. Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, we identified cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1alpha was found within non-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter.

Hyperosmotic Stress Inhibits Insulin Receptor Substrate-1 Function by Distinct Mechanisms in 3T3-L1 Adipocytes

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1074/JBC.M212273200

Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass

Publisher: Elsevier BV

Date: 07-2014

DOI: 10.1016/J.SOARD.2013.12.019

Abstract: Early benefits of Roux-en Y gastric bypass (RYGB) are partly mediated by the caloric restriction that patients undergo before and acutely after the procedure. Altered DNA methylation occurs in metabolic diseases including obesity, as well as in skeletal, muscle eight months after RYGB. The objective of this study was to test whether promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1 A), pyruvate dehydrogenase kinase isozyme-4 (PDK4), transcription factor A (TFAM), interleukin-1 beta (IL1 B), interleukin-6 (IL6) and tumor necrosis factor-α (TNF) is altered in blood after a very low calorie diet (VLCD) or RYGB. Obese nondiabetic patients (n = 18, body mass index [BMI] 42.3 ± 4.9 kg/m(2)) underwent a 14-day VLCD followed by RYGB. Nonobese patients (n = 6, BMI 25.7 ± 2.1 kg/m(2)) undergoing elective cholecystectomy served as controls. DNA methylation of selected promoter regions was measured in whole blood before and after VLCD. A subgroup of seven patients was studied 1-2 days and 12 ± 3 months after RYGB. Promoter methylation was measured using methylated DNA capture and quantitative real-time polymerase chain reaction (PCR). VLCD decreased promoter methylation of PPARGC1 A. Methylation of PPARGC1 A, TFAM, IL1 B, IL6, and TNF promoters was changed two days after RYGB. Similar changes were also seen on day one after cholecystectomy. Moreover, methylation increased in PDK4, IL1 B, IL6, and TNF promoters 12 months after RYGB. RYGB induced more profound epigenetic changes than VLCD in promoters of the tested genes in whole blood. Changes in DNA methylation may contribute to the improved overall metabolic health after RYGB.

C-peptide increases Na,K-ATPase expression via PKC- and MAP kinase-dependent activation of transcription factor ZEB in human renal tubular cells

Publisher: Public Library of Science (PLoS)

Date: 05-12-2011

DOI: 10.1371/JOURNAL.PONE.0028294

Epigenetic reprogramming of immune cells in women with PCOS impact genes controlling reproductive function.

Publisher: The Endocrine Society

Date: 07-08-2019

DOI: 10.1210/JC.2019-01015

Abstract: Polycystic ovary syndrome (PCOS) is a chronic disease affecting reproductive function and whole-body metabolism. Although the etiology is unclear, emerging evidence indicates that the epigenetics may be a contributing factor. To determine the role of global and genome-wide epigenetic modifications in specific immune cells in PCOS compared with controls and whether these could be related to clinical features of PCOS. Cross-sectional study. Women with (n = 17) or without PCOS (n = 17). Recruited from the general community. Isolated peripheral blood mononuclear cells were analyzed using multicolor flow cytometry methods to determine global DNA methylation levels in a cell-specific fashion. Transcriptomic and genome-wide DNA methylation analyses were performed on T helper cells using RNA sequencing and reduced representation bisulfite sequencing. Women with PCOS had lower global DNA methylation in monocytes (P = 0.006) and in T helper (P = 0.004), T cytotoxic (P = 0.004), and B cells (P = 0.03). Specific genome-wide DNA methylation analysis of T helper cells from women with PCOS identified 5581 differentially methylated CpG sites. Functional gene ontology enrichment analysis showed that genes located at the proximity of differentially methylated CpG sites belong to pathways related to reproductive function and immune cell function. However, these genes were not altered at the transcriptomic level. It was shown that PCOS is associated with global and gene-specific DNA methylation remodeling in a cell type–specific manner. Further investigation is warranted to determine whether epigenetic reprogramming of immune cells is important in determining the different phenotypes of PCOS.

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

Publisher: Springer Science and Business Media LLC

Date: 06-11-2018

DOI: 10.1186/S13148-018-0561-5

Epigenetic and Transcriptomic Characterization of Pure Adipocyte Fractions From Obese Pigs Identifies Candidate Pathways Controlling Metabolism

Publisher: Frontiers Media SA

Date: 17-12-2019

DOI: 10.3389/FGENE.2019.01268

DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.METABOL.2014.05.014

Abstract: Obesity is associated with low-grade inflammation and the infiltration of immune cells in insulin-sensitive tissues, leading to metabolic impairment. Epigenetic mechanisms control immune cell lineage determination, function and migration and are implicated in obesity and type 2 diabetes (T2D). The aim of this study was to determine the global DNA methylation profile of immune cells in obese and T2D in iduals in a cell type-specific manner. Fourteen obese subjects and 11 age-matched lean subjects, as well as 12 T2D obese subjects and 7 age-matched lean subjects were recruited. Global DNA methylation levels were measured in a cell type-specific manner by flow cytometry. We validated the assay against mass spectrometry measures of the total 5-methylcytosine content in cultured cells treated with the hypomethylation agent decitabine (r=0.97, p<0.001). Global DNA methylation in peripheral blood mononuclear cells, monocytes, lymphocytes or T cells was not altered in obese or T2D subjects. However, analysis of blood fractions from lean, obese, and T2D subjects showed increased methylation levels in B cells from obese and T2D subjects and in natural killer cells from T2D patients. In these cell types, DNA methylation levels were positively correlated with insulin resistance, suggesting an association between DNA methylation changes, immune function and metabolic dysfunction. Both obesity and T2D are associated with an altered epigenetic signature of the immune system in a cell type-specific manner. These changes could contribute to the altered immune functions associated with obesity and insulin resistance.

High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1016/J.MOLMET.2015.12.002

Evidence for non-CpG methylation in mammals

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1016/J.YEXCR.2011.08.019

Abstract: In mammals, the existence of cytosine methylation on non-CpG sequences is controversial. Here, we adapted a LuminoMetric-based Assay (LUMA) to determine global non-CpG methylation levels in rodent and human tissues. We observed that <1% cytosines in non-CpG motifs were methylated in 3T3-L1 fibroblasts, whereas 7-13% cytosines in non-CpG motifs were methylated in mouse tissues or embryonic fibroblasts. Analysis of cytosine methylation in human, rat, and mouse tissues by bisulfite sequencing revealed non-CpG methylation levels up to 7.5% of all non-CpG cytosines. These levels dropped to 1.5% when a second round of PCR was performed prior to bisulfite sequencing, providing an explanation for the common underestimation of non-CpG methylation levels. Collectively, our results provide evidence that non-CpG methylation exists at substantial levels in mammals.

Identification of two microRNA nodes as potential cooperative modulators of liver metabolism

Publisher: Wiley

Date: 11-09-2019

DOI: 10.1111/HEPR.13419

Male reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity

Publisher: Springer Science and Business Media LLC

Date: 04-05-2023

DOI: 10.1038/S41467-023-38314-X

Abstract: 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.

OBEDIS Core Variables Project: European Expert Guidelines on a Minimal Core Set of Variables to Include in Randomized, Controlled Clinical Trials of Obesity Interventions

Publisher: S. Karger AG

Date: 2020

DOI: 10.1159/000505342

Abstract: Heterogeneity of interin idual and intrain idual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing – focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of in iduals’ responses to an intervention for obesity – ultimately leading to better patient care and improved obesity outcomes.

Exercise training alters the genomic response to acute exercise in human adipose tissue.

Publisher: Future Medicine Ltd

Date: 08-2018

DOI: 10.2217/EPI-2018-0039

Abstract: Aim: To determine the genomic mechanisms by which adipose tissue responds to acute and chronic exercise. Methods: We profiled the transcriptomic and epigenetic response to acute exercise in human adipose tissue collected before and after endurance training. Results: Although acute exercises were performed at same relative intensities, the magnitude of transcriptomic changes after acute exercise was reduced by endurance training. DNA methylation remodeling induced by acute exercise was more prominent in trained versus untrained state. We found an overlap between gene expression and DNA methylation changes after acute exercise for 32 genes pre-training and six post-training, notably at adipocyte-specific genes. Conclusion: Training status differentially affects the epigenetic and transcriptomic response to acute exercise in human adipose tissue.

Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.MOLMET.2021.101290

Erratum: Altered promoter methylation of PDK4, IL1A, IL6, and TNF after Roux-en y gastric bypass (Surgery for Obesity and Related Diseases (2014) 10 (671-678))

Publisher: Elsevier BV

Date: 05-2015

DOI: 10.1016/J.SOARD.2015.02.012

Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1016/J.CMET.2015.11.004

Abstract: Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity. Comprehensive profiling of the epigenome of sperm from lean and obese men showed similar histone positioning, but small non-coding RNA expression and DNA methylation patterns were markedly different. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure and offers insight into how obesity may propagate metabolic dysfunction to the next generation.

Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

Publisher: Elsevier BV

Date: 2015

DOI: 10.1016/J.CELL.2014.12.025

Methodology for Accurate Detection of Mitochondrial DNA Methylation

Publisher: MyJove Corporation

Date: 20-05-2018

DOI: 10.3791/57772

Non-cell autonomous mechanisms control mitochondrial gene dysregulation in polycystic ovary syndrome

Publisher: Bioscientifica

Date: 2022

DOI: 10.1530/JME-21-0212

Abstract: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo . Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II–V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro , irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Publisher: Wiley

Date: 26-12-2019

DOI: 10.1113/JP278752

Enigma Interacts with Adaptor Protein with PH and SH2 Domains to Control Insulin-Induced Actin Cytoskeleton Remodeling and Glucose Transporter 4 Translocation

Publisher: The Endocrine Society

Date: 11-2006

DOI: 10.1210/ME.2005-0455

Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity

Publisher: Public Library of Science (PLoS)

Date: 29-01-2021

DOI: 10.1371/JOURNAL.PGEN.1009325

Abstract: In response to physical exercise and diet, skeletal muscle adapts to energetic demands through large transcriptional changes. This remodelling is associated with changes in skeletal muscle DNA methylation which may participate in the metabolic adaptation to extracellular stimuli. Yet, the mechanisms by which muscle-borne DNA methylation machinery responds to diet and exercise and impacts muscle function are unknown. Here, we investigated the function of de novo DNA methylation in fully differentiated skeletal muscle. We generated muscle-specific DNA methyltransferase 3A (DNMT3A) knockout mice (mD3AKO) and investigated the impact of DNMT3A ablation on skeletal muscle DNA methylation, exercise capacity and energy metabolism. Loss of DNMT3A reduced DNA methylation in skeletal muscle over multiple genomic contexts and altered the transcription of genes known to be influenced by DNA methylation, but did not affect exercise capacity and whole-body energy metabolism compared to wild type mice. Loss of DNMT3A did not alter skeletal muscle mitochondrial function or the transcriptional response to exercise however did influence the expression of genes involved in muscle development. These data suggest that DNMT3A does not have a large role in the function of mature skeletal muscle although a role in muscle development and differentiation is likely.

Erratum to Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation [Cell Reports 3, (2013) 1020-1027]

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.CELREP.2013.05.017

Sperm epigenetics and influence of environmental factors

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.MOLMET.2018.02.006

Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis

Publisher: Elsevier BV

Date: 02-2022

DOI: 10.1016/J.CMET.2021.12.016

Abstract: Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood s ling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism.

Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes

Publisher: Future Medicine Ltd

Date: 06-2019

DOI: 10.2217/EPI-2019-0055

Abstract: Aim: To investigate the degree by which epigenetic signatures in children from mothers with gestational diabetes mellitus (GDM) are influenced by environmental factors. Methods: We profiled the DNA methylation signature of blood from lean, obese and GDM mothers and their respective newborns. Results: DNA methylation profiles of mothers showed high similarity across groups, while newborns from GDM mothers showed a marked distinct epigenetic profile compared with newborns of both lean and obese mothers. Analysis of variance in DNA methylation levels between newborns showed higher variance in the GDM group. Conclusion: Our results suggest that environmental factors, rather than direct transmission of epigenetic marks from the mother, are involved in establishing the epigenetic signature associated with GDM.

Time-restricted feeding alters lipid and amino acid metabolite rhythmicity without perturbing clock gene expression

Publisher: Springer Science and Business Media LLC

Date: 16-09-2020

DOI: 10.1038/S41467-020-18412-W

Abstract: 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 litude 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.

Centre National Pour La Recherche Scientifique Et Technique

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Centre National Pour La Recherche Scientifique Et Technique

Location: France

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Université De Nice Sophia Antipolis

Location: France

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Université Paul Sabatier

Location: France

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IT University Of Copenhagen

Location: Denmark

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University Of New South Wales

Location: Australia

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Karolinska Institutet

Location: Sweden

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Københavns Universitet

Location: Denmark

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Discovery Projects - Grant ID: DP110103663

Start Date: 2012

End Date: 12-2014

Amount: $320,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP200103542

Start Date: 2020

End Date: 12-2024

Amount: $493,000.00

Funder: Australian Research Council