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Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci ( P  < 5 × 10 −8 ), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis. Genetic correlates of obesity In the second of two Articles in this issue from the GIANT Consortium, Elizabeth Speliotes and collegues conducted a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), commonly used to define obesity and assess adiposity, to find 97 BMI-associated loci, of which 56 were novel. Many of these loci have significant effects on other metabolic phenotypes. The 97 loci account for about 2.7% of BMI variation, and genome-wide estimates suggest common variation accounts for more than 20% of BMI variation. Pathway analyses implicate the central nervous system in obesity susceptibility including synaptic function, glutamate signaling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

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.

A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. ClinicalTrials.gov NCT00633282.

ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.

BackgroundThe effects of probiotic Bifidobacterium animalis subsp. lactis CECT 8145 (Ba8145) and those of its heat-killed form (h-k Ba8145) on human anthropometric adiposity biomarkers are unknown.ObjectiveTo assess the effect of Ba8145 and h-k Ba8145 ingestion on anthropometric adiposity biomarkers.DesignRandomized, parallel, double-blind, placebo-controlled trial with abdominally obese individuals. Participants (n = 135) consumed 1 capsule/day containing 1010 colony forming unit (CFU) of Ba8145, 1010 CFU of h-k Ba8145, or placebo (maltodextrin) for 3 months.ResultsBa8145 ingestion decreased waist circumference, waist circumference/height ratio, and Conicity index (P < 0.05) versus its baseline. Changes versus the placebo group reached significance (P < 0.05) after the h-k Ba8145 treatment. Ba8145 decreased the body mass index compared with baseline and placebo group (P < 0.05). The decrease in visceral fat area after Ba8145 treatments reached significance (P < 0.05) only after h-k Ba8145. When analyses by gender were performed, significance remained only for women. Diastolic blood pressure and HOMA index decreased (P < 0.05) after h-k Ba8145. Gut microbiome analyses showed an increase in Akkermansia spp. after Ba8145 treatment, particularly in the live form, which was inversely related to weight (P = 0.003).ConclusionsIn abdominally obese individuals, consumption of Ba8145, both as viable and mainly as heat-killed cells, improves anthropometric adiposity biomarkers, particularly in women. An increase in the gut Akkermansia genus appears as a possible mechanism involved. Our results support Ba8145 probiotic as a complementary strategy in obesity management.

Background We investigated whether Lactobacillus plantarum strain LMT1-48, isolated from Korean fermented foods and newborn feces, is a suitable probiotic supplement to treat overweight subjects. Methods In this randomized, double-blind, placebo-controlled clinical trial, 100 volunteers with a body mass index of 25 to 30 kg/m2 were assigned randomly (1:1) to receive 2×1010 colony forming units of LMT1-48 or to a placebo treatment group. Body composition was measured by dual-energy X-ray absorptiometry, and abdominal visceral fat area (VFA) and subcutaneous fat area were measured by computed tomography scanning. Changes in body fat, VFA, anthropometric parameters, and biomarkers were compared between the two treatment groups (ClinicalTrials.gov number: NCT03759743). Results After 12 weeks of treatment, the body weight decreased significantly from 76.6±9.4 to 75.7±9.2 kg in the LMT1-48 group but did not change in the placebo group (P=0.022 between groups). A similar pattern was found in abdominal VFA between the two groups (P=0.041). Serum insulin levels, the corresponding homeostasis model assessment of insulin resistance, and leptin levels decreased in the LMT1-48 group but increased in the placebo group (all P<0.05). Decrease in body weight and body mass index by treatment with LMT1-48 was correlated with increase in Lactobacillus levels significantly. LMT1-48 also increased Oscillibacter levels significantly, which were negatively correlated with triglyceride and alanine transaminase levels. Conclusion Administration of LMT1-48 decreased body weight, abdominal VFA, insulin resistance, and leptin levels in these subjects with overweight, suggesting its anti-obesogenic therapeutic potential.

Background South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. Methods In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. Results In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (− 3.9 ± 3.6 kg vs − 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): − 3.5 kg; 95% CI [− 5.3, − 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (− 23 ± 27 cm 2 vs − 2 ± 17 cm 2 ; mean change from baseline (liraglutide vs placebo): − 17 cm 2 ; 95% CI [− 32, − 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (− 1.0 ± 0.8% (− 10.5 ± 9.1 mmol/mol)) vs (− 0.6 ± 0.8% (− 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): − 0.6% (− 6.5 mmol/mol); 95% CI [− 1.1, − 0.1 (− 11.5, − 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (β: 0.165 mmol/mol (0.015%) per 1 cm 2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). Conclusions While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016

Aims/hypothesisOffspring of obese women are at increased risk of features of the metabolic syndrome, including obesity and diabetes. Lifestyle intervention in pregnancy might reduce adverse effects of maternal obesity on neonatal adiposity.MethodsIn the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention (DALI) lifestyle trial, 436 women with a BMI ≥29 kg/m2 were randomly assigned to counselling on healthy eating (HE), physical activity (PA) or HE&PA, or to usual care (UC). In secondary analyses of the lifestyle trial, intervention effects on neonatal outcomes (head, abdominal, arm and leg circumferences and skinfold thicknesses, estimated fat mass, fat percentage, fat-free mass and cord blood leptin) were assessed using multilevel regression analyses. Mediation of intervention effects by lifestyle and gestational weight gain was assessed.ResultsOutcomes were available from 334 neonates. A reduction in sum of skinfolds (−1.8 mm; 95% CI −3.5, −0.2; p = 0.03), fat mass (−63 g; 95% CI −124, −2; p = 0.04), fat percentage (−1.2%; 95% CI −2.4%, −0.04%; p = 0.04) and leptin (−3.80 μg/l; 95% CI −7.15, −0.45; p = 0.03) was found in the HE&PA group, and reduced leptin in female neonates in the PA group (−5.79 μg/l; 95% CI −11.43, −0.14; p = 0.05) compared with UC. Reduced sedentary time, but not gestational weight gain, mediated intervention effects on leptin in both the HE&PA and PA groups.Conclusions/interpretationThe HE&PA intervention resulted in reduced adiposity in neonates. Reduced sedentary time seemed to drive the intervention effect on cord blood leptin. Implications for future adiposity and diabetes risk of the offspring need to be elucidated.Trial registrationISRCTN70595832.

Abstract Context Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations. Objective To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men. Design, Participants, and Intervention 177 men aged 60 to 80 were randomly assigned to receive goserelin acetate plus either 0 (placebo), 1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks or placebos for both medications (controls). Primary Outcomes Changes in serum C-telopeptide (CTX), total body fat by dual energy X-ray absorptiometry, and self-reported sexual desire. Results Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0 to 99, 100 to 199, 200 to 299, or 300 to 499 ng/dL, whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0 to 99 or 100 to 199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were <100 ng/dL. Conclusion Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.

Visceral adipose tissue (VAT)—fat stored around the internal organs—has been suggested as an independent risk factor for cardiovascular and metabolic disease1–3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74–0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48–12.0) in females and an odds ratio of 2.50 (95% CI = 1.98–3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.