SUN-092 Distinct Changes in Gut Microbiota Are Associated with Estradiol-Mediated Protection from Diet-Induced Obesity in Female Mice

Due to an aging-associated decrease in ovarian estrogens, postmenopausal women tend to gain weight, which predisposes them to developing cardiovascular disease, type 2 diabetes, chronic inflammation, and cancer. Estradiol replacement has been shown to protect postmenopausal women and ovariectomized rodents from obesity and metabolic disorders, but the underlying mechanisms are not fully understood. In addition to estrogens, gut microbiota are also known to regulate energy homeostasis. In this study, we investigated the effects of estrogens on gut microbiota and energy metabolism in female mice on standard diet (SD) or high-fat diet (HFD). Ovariectomized adult C57BL6/J mice received implants containing estradiol (E2) or vehicle (Veh) (n=6/group). Mice were fed SD for the first two weeks and then switched to HFD for the remaining four weeks of the study. To investigate the effects of E2 and diet on gut microbiota, fresh fecal samples were collected at various times during SD and HFD for 16S rRNA gene sequencing. Using metabolic cages, the effects of E2 and HFD on energy balance were assessed longitudinally by measuring food intake, energy expenditure, and physical activity. In addition, plasma glucose, insulin, leptin, resistin and cytokines were measured during SD and HFD. Insulin sensitivity and glucose metabolism were assessed during a 2-hr hyperinsulinemic-euglycemic clamp in awake mice at the end of HFD. Our results indicate that chronic E2 treatment protected the ovariectomized mice from HFD-induced obesity, mostly due to increases in energy expenditure and physical activity. These effects were associated with altered bacterial communities; E2 increased the relative abundance of the mucin-producing microbes Akkermansia spp. (phylum Verrucomicrobia) that are responsible for the integrity of the gut epithelial barrier. Veh mice had increased the relative abundances of Erysipleotrichaceae and Streptococcaceae (family) and their lower taxa. HFD profoundly altered microbial diversity by reducing species richness, increasing evenness and altering relative abundances of multiple taxa. HFD was associated with increased Bacteriodes (phylum Bacteriodetes) and Clostridia (phylum Firmicutes), which are responsible for HFD-induced weight gain in humans. The relative abundance of Erysipleotrichi was positively correlated with HFD, but negatively correlated with E2 treatment, suggesting a potential causal relationship between this taxon and obesity. E2-treated mice were more insulin-sensitive with marked increases in whole body glucose turnover and glycogen synthesis after HFD. Taken together, these results suggest that changes in gut microbiota contribute to E2-mediated protection against diet-induced obesity and metabolic dysregulation. These findings may provide important insights for potential microbial targets for the treatment of metabolic disorders in women.