Alteration of gut microbiota affects expression of adiponectin and resistin through modifying DNA methylation in high-fat diet-induced obese mice.

BACKGROUND Adiponectin and resistin are typically secreted by the adipose tissue and are abnormally expressed in obesity. However, the underlying influential factors and mechanisms are to be elucidated. It is well known that the expression of genes is regulated by epigenetics while gut microbiota participates in epigenetic processes through its metabolites such as folate, biotin, and short-chain fatty acids (SCFAs). Therefore, we supposed that alteration of gut microbiota might affect the transcriptional expression of adiponectin and resistin through epigenetic regulation in obesity. METHODS C57BL/6J mice were fed either a high-fat diet (34.9% fat by wt., 60% kcal) or a normal-fat diet (4.3% fat by wt., 10% kcal) for 16 weeks, with ampicillin and neomycin delivered via drinking water to interfere with gut microbiota development. Fecal microbiota was analyzed by 16S rRNA high-throughput sequencing. The mRNA expression levels of genes were measured by real-time quantitative RT-PCR. SCFA contents in feces were examined using gas chromatography. RESULTS Alteration of the gut microbiota induced by antibiotic use, characterized by a dramatic reduction of the phylum Firmicutes and Actinobacteria and an increase of Proteobacteria with reductions of genera including Lactobacillus, norank_f_Bacteroidales_S24-7_group, Alistipes, Desulfovibrio, Helicobacter, etc., and increases in Bacteroides, Enterobacter, Klebsiella, inhibited the body weight gain in mice fed the high-fat diet instead of the normal-fat diet. The mRNA expression of adiponectin and resistin was upregulated by antibiotic use in mice fed the high-fat diet, accompanied by increased expression of fat oxidation and thermogenesis-related genes (PPAR-α, Pgc-1α, and Atgl) in the fat and/or liver, whereas no change in the expression of adiponectin and resistin was found in mice fed the normal-fat diet. Furthermore, antibiotic use reduced DNA methylation fractions of the adiponectin and resistin promoters and downregulated the expression of DNA methyltransferase 1 and 3a (DNMT1 and DNMT3a) with the high-fat diet feeding. CONCLUSION Alteration of gut microbiota induced by antibiotic use may affect the expression of adiponectin and resistin in mice fed the high-fat diet by modifying promoter DNA methylation, thus leading to increased fatty acid oxidation and less body weight gain.