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Background: Lower serum 25-hydroxyvitamin D [25(OH)D] is associated with greater adiposity and adverse cardiometabolic risk profile. The evidence is inconsistent among South Asian Indians. We aimed to examine associations between 25(OH)D and cardiovascular (CVD) risk markers in a rural and urban cohort from South India., Subjects/methods: In this cross sectional study, 373 individuals (men, n = 205) underwent detailed CVD risk marker assessment including anthropometry [body mass index (BMI), waist, (WC) and hip circumferences (HC)], body composition analysis using dual energy x-ray absorptiometry (DXA), blood pressure and biochemical analysis (glucose, insulin and lipids). The distribution of CVD risk factors were compared across serum 25(OH)D levels, stratified as deficiency (<20 ng/ml), insufficiency (20 to 29 ng/ml) and normal (≥30 ng/ml) levels. Multiple regression analysis, adjusting for potential confounders, was used to study associations of 25(OH)D with adiposity and cardiometabolic traits., Results: The mean and standard deviation (SD) of age, BMI and 25(OH)D levels were 41.4 (1.1) years, 25.5 (4.8) kg/m2 and 23.4 (10.4) ng/ml respectively. The prevalence of 25(OH)D deficiency was 39.9% in this cohort. Individuals in the 25(OH)D deficiency category had significantly higher mean (SD) BMI [26.6 (5.1) kg/m2], waist circumference [89.9 (12.5) cm] and total fat mass [20.6 (7.9) kg] compared with the Vitamin D sufficient group [BMI: 24.0 (4.4); WC 84.7 (12.0); total fat mass: 15.2 (6.8)]. Significantly inverse associations were observed with DXA measured total and regional fat depots with 25(OH)D levels, while anthropometric indices of adiposity showed significant inverse association only in women. After adjusting for total fat mass, no significant associations were observed between 25(OH)D and the cardiometabolic traits., Conclusions: Our results confirm that lower 25(OH)D is independently associated with both total and regional adiposity, but not with cardiometabolic traits, in this population., Competing Interests: The authors have declared that no competing interests exist.

Aims/hypothesis: Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans., Methods: Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m 2 ) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME., Results: A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses., Conclusions/interpretation: Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.

Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue-specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype.