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A large-scale epigenome-wide association study identifies changes in DNA methylation associated with body mass index in blood and adipose tissue, and correlates DNA methylation sites with high risk of incident type 2 diabetes. Body fat and diabetes risk Obesity is a major risk factor for type 2 diabetes and related metabolic disorders. Genetic association studies have identified genomic loci associated with obesity, and recent studies have also suggested associations with DNA methylation. These authors report an epigenome-wide association study for body mass index (BMI), identifying an association with DNA methylation at 187 loci in blood and adipose tissue. They find that these methylation changes are secondary to adiposity and are also associated with an increased risk of developing type 2 diabetes, independent of conventional risk factors. Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances 1 , 2 . Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation 3 , 4 , 5 , 6 , a key regulator of gene expression and molecular phenotype 7 . Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P  < 1 × 10 −7 , range P  = 9.2 × 10 −8 to 6.0 × 10 −46 ; n  = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues ( P  < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci ( P  < 9.0 × 10 −6 , range P  = 5.5 × 10 −6 to 6.1 × 10 −35 , n  = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P  = 1.1 × 10 −54 ). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N  = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies. Psychiatric disorders are often accompanied by alterations in BMI and body composition due to changes in eating behaviour and physical activity. Here, Hübel et al. study the genetic overlap between these traits and find that genetic correlations between psychiatric disorders and body composition are sex-specific and evident only in adulthood.

Weight loss (WL) differences between isocaloric high-carbohydrate and high-fat diets are generally small; however, individual WL varies within diet groups. Genotype patterns may modify diet effects, with carbohydrate-responsive genotypes losing more weight on high-carbohydrate diets (and vice versa for fat-responsive genotypes). We investigated whether 12-week WL (kg, primary outcome) differs between genotype-concordant and genotype-discordant diets. In this 12-week single-center WL trial, 145 participants with overweight/obesity were identified a priori as fat-responders or carbohydrate-responders based on their combined genotypes at ten genetic variants and randomized to a high-fat (n = 73) or high-carbohydrate diet (n = 72), yielding 4 groups: (1) fat-responders receiving high-fat diet, (2) fat-responders receiving high-carbohydrate diet, (3) carbohydrate-responders receiving high-fat diet, (4) carbohydrate-responders receiving high-carbohydrate diet. Dietitians delivered the WL intervention via 12 weekly diet-specific small group sessions. Outcome assessors were blind to diet assignment and genotype patterns. We included 122 participants (54.4 [SD:13.2] years, BMI 34.9 [SD:5.1] kg/m 2 , 84% women) in the analyses. Twelve-week WL did not differ between the genotype-concordant (−5.3 kg [SD:1.0]) and genotype-discordant diets (−4.8 kg [SD:1.1]; adjusted difference: −0.6 kg [95% CI: −2.1,0.9], p  = 0.50). With the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater WL on genotype-concordant diets. ClinicalTrials identifier: NCT04145466. Genotype patterns may modify diet effects on weight loss, with greater weight loss on genotype-concordant diets. Here, the authors show that with the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater weight loss on genotype-concordant diets.

Recent evidence suggests that the fat mass and obesity-associated gene (FTO) genotype may interact with dietary intakes in relation to adiposity. We tested the effect of FTO variant on weight loss in response to 2-year diet interventions. FTO rs1558902 was genotyped in 742 obese adults who were randomly assigned to one of four diets differing in the proportions of fat, protein, and carbohydrate. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography. We found significant modification effects for intervention varying in dietary protein on 2-year changes in fat-free mass, whole body total percentage of fat mass, total adipose tissue mass, visceral adipose tissue mass, and superficial adipose tissue mass (for all interactions, P < 0.05). Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. Likewise, significant interaction patterns also were observed at 6 months. Our data suggest that a high-protein diet may be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902.

Abstract Context Maternal dysglycaemia and prepregnancy obesity are associated with adverse offspring outcomes. Epigenetic mechanisms such as DNA methylation (DNAm) could contribute. Objective To examine relationships between maternal glycaemia, insulinemic status, and dietary glycemic indices during pregnancy and an antenatal behavioral-lifestyle intervention with newborn DNAm. Methods We investigated 172 women from a randomized controlled trial of a lifestyle intervention in pregnant women who were overweight or obese. Fasting glucose and insulin concentrations and derived indices of insulin resistance (HOMA-IR), β-cell function (HOMA-%B), and insulin sensitivity were determined at baseline (15) and 28 weeks’ gestation. Dietary glycemic load (GL) and index (GI) were calculated from 3-day food diaries. Newborn cord blood DNAm levels of 850K CpG sites were measured using the Illumina Infinium HumanMethylationEPIC array. Associations of each biomarker, dietary index and intervention with DNAm were examined. Results Early pregnancy HOMA-IR and HOMA-%B were associated with lower DNAm at CpG sites cg03158092 and cg05985988, respectively. Early pregnancy insulin sensitivity was associated with higher DNAm at cg04976151. Higher late pregnancy insulin concentrations and GL scores were positively associated with DNAm at CpGs cg12082129 and cg11955198 and changes in maternal GI with lower DNAm at CpG cg03403995 (Bonferroni corrected P < 5.99 × 10−8). These later associations were located at genes previously implicated in growth or regulation of insulin processes. No effects of the intervention on cord blood DNAm were observed. None of our findings were replicated in previous studies. Conclusion Among women who were overweight or obese, maternal pregnancy dietary glycemic indices, glucose, and insulin homeostasis were associated with modest changes in their newborn methylome. Trial registration ISRCTN29316280

Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18–40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care. Baseline subcutaneous adipose tissue gene expression was related to weight change after the lifestyle intervention. A total of 55 obese/overweight women provided subcutaneous adipose samples at study entry. Weight loss was significant after behavioral modification (−2.2%, p = 0.0014), while there was no significant weight loss in the control group (−1.1%, p = 0.12). In microarray analysis of adipose samples, expression of 40 genes differed significantly between subgroups of those with the greatest weight loss or weight gain. 10 genes were involved in metabolic pathways including glutathione metabolism, gluconeogenesis, and pyruvate metabolism. Results were confirmed by real-time polymerase chain reaction (RT-PCR) in all 55 subjects. Expressions of GSTM5, ANLN, and H3C2 correlated with weight change (R = −0.41, p = 0.002; R = −0.31, p = 0.023 and R = −0.32, p = 0.016, respectively). GSTM5, involved in glutathione metabolism, was the strongest predictor of weight loss, and together with baseline waist-hip ratio (WHR) explained 31% of the variation in body weight change. This study shows that baseline subcutaneous adipose tissue genes play a role for body weight outcome in response to lifestyle intervention in overweight/obese women with PCOS.

Nutrigenetic parameters influence quality of life (QoL) by highlighting how genetic variations affect weight management and allow for personalized dietary recommendations that enhance health status. The present study investigates the effect of a dietary intervention on the SF-12 physical (SF-PCS-12) and mental components (SF-MCS-12) of adults with overweight and obesity, at high genetic risk for increased Body Mass Index (BMI). Data from 80 participants were analyzed, all of whom were randomized at baseline to follow either a high-protein or high-carbohydrate hypocaloric diet for three months. QoL was measured using the SF-12 questionnaire, with self-reported assessments conducted at baseline and at the end of each intervention month. Differences pre- and post- intervention were assessed using the Wilcoxon signed-rank test. Additionally, 10 BMI-related variants were investigated for potential effects on the observed differences in SF-PCS-12 and SF-MCS-12, via linear regressions using the Plink software. Overall, no statistically significant differences were observed in SF-PCS-12 and SF-MCS-12 scores post-intervention. However, while SF-PCS-12 showed less improvement in high-risk individuals, participants with high-BMI risk alleles demonstrated a notable increase in SF-MCS-12 scores. This finding suggests that dietary interventions may positively impact mental health, even in individuals with a heightened genetic risk for obesity.

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

Dietary fats influence gene expression and several metabolic pathways. Therefore, it is crucial to study the role of personal genotypes in the interaction between fat consumption and cardiometabolic markers. This research aimed to determine the interaction of the rs708272 polymorphism of CETP and the fatty acid intake with changes in the HOMA-IR in adults living with overweight or obesity. The current study was a secondary analysis of an 8-week controlled clinical trial. The final sample for this analysis comprised 78 Mexican adults with the Cholesteryl Ester Transfer Protein (CETP) rs708272 polymorphism who followed a dietary intervention. Using an interaction analysis, we evaluated the fatty acid intake and the genotypes of rs708272, with changes in blood glucose, insulin, and the HOMA-IR from baseline to endpoint. Our findings suggest a significant interaction between the trans fatty acid intake and the GG genotype with changes in glucose (p = 0.024), insulin (p = 0.004), and the HOMA-IR (p = 0.002). The higher the consumption of trans fatty acids, the less these markers of glucose metabolism were reduced. carriers of the GG genotype may benefit from limiting dietary trans fatty acid intake, as there was no reduction in plasma glucose and insulin despite a hypocaloric dietary intervention in adults with overweight and obesity.

Background/objectives: Milk provides protein and micronutrients, and is recommended by some dietary guidelines, particularly for bone health. Meta-analysis of small randomized controlled trials suggests that milk may increase bone mineral density, but they are very heterogeneous. No randomized controlled trial has assessed the effects of milk on major chronic diseases. Previous Mendelian randomization studies of milk did not consider bone health, found no effects on ischemic heart disease (IHD) or type 2 diabetes (T2D) but higher body mass index. Using larger genetic studies, we estimated the effects of milk on osteoporosis, IHD, T2D, adiposity, lipids and glycemic traits. Subjects/methods: Instrumental variable analysis based on a genetic variant endowing lactase persistence (rs4988235 ( MCM6 )) was used to obtain estimates for osteoporosis (GEFOS), IHD (CARDIoGRAMplusC4D), T2D (DIAGRAM), adiposity (GIANT), lipids (GLGC) and glycaemic traits (MAGIC). Eye color was a negative control for IHD, as it mirrors the distribution of lactase persistence and IHD in Western Europe. Results: Genetically predicted adult milk consumption was not clearly associated with bone mineral density, IHD (odds ratio (OR): 1.03 per s.d., 95% confidence interval (CI): 0.95–1.12) and or T2D (OR: 0.92, 95% CI: 0.83–1.02) but was associated with higher log-transformed fasting insulin (0.05, 95% CI: 0.02–0.07) and body mass index (0.06, 95% CI: 0.03–0.09). Genetically predicted eye color was not associated with IHD. Conclusions: The lack of association of genetically predicted milk consumption with bone health, IHD or T2D suggests few beneficial effects but is more consistent with milk promoting adiposity.