Bisphenol A increases fat mass in adipose tissue by disturbing gut microbiota-dependent bile acid metabolism and TGR5/UCP1 signaling pathways in CD-1 mice

Disorder of gut microbiota-mediated bile acid (BA) metabolism plays a pivotal role in the pathogenesis of obesity. Our previous research showed that bisphenol A (BPA) exposure induced hepatic fat accumulation and gut microbiota dysbiosis. However, whether the gut microbiota-dependent BA metabolism alteration is involved in BPA-induced fat accumulation and obesity remains elusive. This study aimed to investigate the gut microbiota-dependent metabolic mechanism of obesity induced by BPA. Male CD-1 mice were exposed to a low dose of BPA (50 μg/kg/day) for six months. Our findings demonstrated that BPA exposure significantly augmented the fat mass of both brown and white adipose tissue, along with the proportion of adipose tissue weight relative to body weight. Furthermore, BPA reduced the relative abundance of Bacteroides, Parabacteroides, and Akkermansia, which are associated with BA metabolism. Additionally, serum levels of lithocholic acid, the most potent activator of Takeda G protein-coupled receptor 5 (TGR5), and TGR5 expression in adipose tissue were substantially diminished following BPA exposure. Inhibition of TGR5 reduced cyclic adenosine monophosphate levels, subsequently decreasing the expression of iodothyronine deiodinase 2 and fibroblast growth factor 21. These changes down-regulated the expression of uncoupling protein 1 (UCP1), ultimately leading to reduced energy expenditure and increased fat mass. Moreover, further fecal microbiota transplantation and microbiota elimination confirmed the role of gut microbiota in BPA-induced adverse effects. Collectively, our study demonstrated that the suppression of gut microbiota-BA-TGR5/UCP1 signaling pathways may constitute a potential mechanism underlying BPA-induced fat mass gain, providing a novel target for the prevention of BPA-induced obesity.