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Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1 , which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Unpredictable stressors have been used to assess the effect of stress on energy metabolism in obesity-prone (C57BL6J) and obesity-resistant (AJ) mice. Mice were exposed for 25 days to a stress protocol. Both strains of mice were divided into groups of control and stressed mice, which had access to either a high-fat or a high-carbohydrate diet. Twenty-four hours after the last session of stress, mice were sacrificed for blood and brain collections. Insulin, corticosterone, and glucose concentrations in plasma were measured, and expressions of corticotropin-releasing factor (CRF) in the paraventricular hypothalamic nucleus (PVH) and the central amygdala (CeA) were determined by in situ hybridization. Stressed mice in all groups had lower body fat contents than control mice, and all mice fed with the high-fat diet had heavier retroperitoneal and inguinal fat pads than mice fed with carbohydrate. CRF mRNA level in the CeA was lower in B6 mice than in AJ mice. Stressed mice had a lower expression of CRF in the CeA than control mice. In conclusion, chronic stress reduces body fat content in obesity-prone as well as in obesity-resistant mice. [Copyright &y& Elsevier]