BackgroundType 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insulin secretion and insulin resistance. Genome-wide association studies (GWAS) were expected to resolve a large part of the genetic component of diabetes; yet, the single nucleotide polymorphisms identified by GWAS explain less than 20% of the estimated heritability for T2D. There was subsequently a need to look elsewhere to find disease-causing factors. Mechanisms mediating the interaction between environmental factors and the genome, such as epigenetics, may be of particular importance in the pathogenesis of T2D.Scope of ReviewThis review summarizes knowledge of the impact of epigenetics on the pathogenesis of T2D in humans. In particular, the review will focus on alterations in DNA methylation in four human tissues of importance for the disease; pancreatic islets, skeletal muscle, adipose tissue, and the liver. Case–control studies and studies examining the impact of non-genetic and genetic risk factors on DNA methylation in humans will be considered. These studies identified epigenetic changes in tissues from subjects with T2D versus non-diabetic controls. They also demonstrate that non-genetic factors associated with T2D such as age, obesity, energy rich diets, physical activity and the intrauterine environment impact the epigenome in humans. Additionally, interactions between genetics and epigenetics seem to influence the pathogenesis of T2D.ConclusionsOverall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D.

This study showed both cross-sectional and longitudinal associations between the inflammatory potential of the diet and telomere shortening in subjects with a high cardiovascular disease risk. Our findings are consistent with, but do not show, a beneficial effect of adherence to an anti-inflammatory diet on aging and health by slowing down telomere shortening. These results suggest that diet might play a key role as a determinant of TL through proinflammatory or anti-inflammatory mechanisms. This trial was registered at controlled-trials.com as ISRCTN35739639.

ContextTelomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents.ObjectiveTo evaluate the association between telomere length (TL) and adiposity markers in overweight/obese adolescents after an intensive program. We hypothesize that greater TL at baseline would predict a better response to a weight loss treatment.Design, Setting, Patients and InterventionThe EVASYON is a multidisciplinary treatment program for adolescents with overweight and obesity that is aimed at applying the intervention to all possibly involved areas of the individual, such as dietary habits, physical activity and cognitive and psychological profiles. Seventy-four participants (36 males, 38 females, 12–16 yr) were enrolled in the intervention program: 2 months of an energy-restricted diet and a follow-up period (6 months).Main OutcomeTL was measured by quantitative real-time polymerase chain reaction at baseline and after 2 months; meanwhile, anthropometric variables were also assessed after 6 months of follow-up.ResultsTL lengthened in participants during the intensive period (+1.9±1.0, p<0.001) being greater in overweight/obese adolescents with the shortest telomeres at baseline (r = −0.962, p<0.001). Multivariable linear regression analysis showed that higher baseline TL significantly predicted a higher decrease in body weight (B = −1.53, p = 0.005; B = −2.25, p = 0.047) and in standard deviation score for body mass index (BMI-SDS) (B = −0.22, p = 0.010; B = −0.47, p = 0.005) after the intensive and extensive period treatment respectively, in boys.ConclusionOur study shows that a weight loss intervention is accompanied by a significant increase in TL in overweight/obese adolescents. Moreover, we suggest that initial longer TL could be a potential predictor for a better weight loss response.

It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in Spanish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length.

Background: Telomeres are nucleoprotein structures that protect the ends of eukaryote

BackgroundHuman skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.MethodsWe used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.ResultsWe observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.ConclusionsOur study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0792-x) contains supplementary material, which is available to authorized users.

The present study analyses the gene expression profile of peripheral blood mononuclear cells (PBMC) from obese boys. The aims of the present study were to identify baseline differences between low responders (LR) and high responders (HR) after 10 weeks of a moderate energy-restricted dietary intervention, and to compare the gene expression profile between the baseline and the endpoint of the nutritional intervention. Spanish obese boys (age 10-14 years) were advised to follow a 10-week moderate energy-restricted diet. Participants were classified into two groups based on the association between the response to the nutritional intervention and the changes in BMI standard deviation score (BMI-SDS): HR group (n 6), who had a more decreased BMI-SDS; LR group (n 6), who either maintained or had an even increased BMI-SDS. The expression of 28 869 genes was analysed in PBMC from both groups at baseline and after the nutritional intervention, using the Affymetrix Human Gene 1.1 ST 24-Array plate microarray. At baseline, the HR group showed a lower expression of inflammation and immune response-related pathways, which suggests that the LR group could have a more developed pro-inflammatory phenotype. Concomitantly, LEPR and SIRPB1 genes were highly expressed in the LR group, indicating a tendency towards an impaired immune response and leptin resistance. Moreover, the moderate energy-restricted diet was able to down-regulate the inflammatory 'mitogen-activated protein kinase signalling pathway' in the HR group, as well as some inflammatory genes (AREG and TNFAIP3). The present study confirms that changes in the gene expression profile of PBMC in obese boys may help to understand the weightloss response. However, further research is required to confirm these findings.

ContextEpigenetics may contribute to sex-specific differences in human liver metabolism.ObjectiveTo study the impact of sex on DNA methylation and gene expression in human liver.Design/SettingCross-sectional, Kuopio Obesity Surgery Study.Participants/InterventionWe analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)–cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants.ResultsFemales displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles.ConclusionsHuman liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.