Curcumin Inhibits Bisphenol A-Induced Fat Mass Gain by Enhancing White Adipose Tissue Browning via Modulating Gut Microbiota-Dependent Bile Acid Metabolism in CD-1 Mice

Chronic exposure to low-dose bisphenol A (BPA) has emerged as a pressing worldwide public health concern. Our previous work demonstrated that low-dose BPA exposure caused gut microbiota dysbiosis and liver fat accumulation. Curcumin is a polyphenol extracted from the rhizome of turmeric and has an inhibitory effect on liver fat accumulation and obesity. This study aimed to investigate the protective effects of curcumin against BPA-induced fat mass gain and obesity and gut microbiota-dependent bile acid (BA) metabolic mechanism. Male CD-1 mice were fed a diet containing a low dose of BPA (50 µg/kg/day) with or without 0.1% w/w curcumin for 24 weeks. Curcumin supplementation markedly decreased the fat mass of inguinal white adipose tissue (iWAT) and the ratio of iWAT weight to body weight in BPA-exposed mice. Curcumin-treated mice exhibited decreased Firmicutes/Bacteroidetes ratio and increased relative abundance of <i>Bacteroides</i>, <i>Parabacteroides,</i> and <i>Akkermansia</i>, which are related to BA metabolism. Moreover, serum levels of lithocholic acid, the most potent activator of Takeda G protein-coupled receptor 5 (TGR5), and TGR5 expression in iWAT were significantly increased following curcumin intervention. Activation of TGR5 elevated cyclic adenosine monophosphate levels, subsequently up-regulating the expression of iodothyronine deiodinase 2 and fibroblast growth factor 21. These changes increased the expression of uncoupling protein 1 (UCP1), ultimately leading to enhanced iWAT browning and reduced fat mass in iWAT. These results indicated that curcumin suppressed BPA-induced fat mass gain by enhancing iWAT browning by activating gut microbiota-BA-TGR5/UCP1 pathways, supporting its potential as a nutritional therapy for BPA-induced obesity.