Obeticholic acid ameliorates obesity and hepatic steatosis by activating brown fat

Obeticholic acid (OCA) is exemplified as a potent drug for treating primary biliary cirrhosis and nonalcoholic fatty liver disease by inhibiting bile acid synthesis. However, it remains unclear whether the effect of OCA is mediated by the function of brown adipose tissue (BAT). In the present study, brown adipogenesis differentiation in vitro and db/db mouse model treated with OCA were used to assess the anti-obesity function by body weight tracking, O(2) consumption, food intake, physical activity, glucose tolerance tests. In addition, uncoupling protein 1 (Ucp1) protein expression in brown adipose tissue was measured by western blotting, morphometry of brown adipose tissue was analyzed by hematoxylin and eosin staining. Hepatic steatosis was detected by Oil-Red O staining and serological analysis was performed to assess the effect of OCA on hyperlipidemia. OCA treatment enhanced brown adipocyte cell differentiation and upregulated the expression of the BAT-specific gene Ucp1) in C3H10T1/2 cells in vitro. Consistent with these findings, OCA increased whole-body energy metabolism and glucose homeostasis by enhancing BAT activity in vivo, and ultimately decreased body weight gain in db/db mice. In addition, the results demonstrated that spontaneous hepatic steatosis in db/db mice was ameliorated following OCA treatment. In summary, OCA functioned as a BAT activator to help ameliorate obesity and maintain glucose homeostasis in db/db mice. The present results may provide a novel potential therapeutic approach to activate brown fat in patients with obesity and other metabolic disorders.