Rifampicin prevents diet-induced obesity through Sirt6-dependent lipolysis, adipocyte browning and lipogenesis inhibition

Rifampicin (RFP) is a semi-synthetic macrocyclic broad-spectrum antibiotic known for its ability to inhibit bacterial proliferation. However, its potential role of obesity treatment has not been explored. We unveil a novel function of rifampicin using 3T3-L1 adipocytes and high-fat diet (HFD)-fed mice. Rifampicin upregulates Sirt6 expression both in vitro and in vivo. Furthermore, rifampicin inhibits 3T3-L1 preadipocyte differentiation and lipid accumulation by suppressing lipogenesis and enhancing lipolysis. Oral administration of rifampicin effectively inhibits body weight gain in HFD-fed mice. Mechanistically, rifampicin significantly suppresses lipogenesis, and enhances lipolysis, energy expenditure and the white adipose tissue browning-related pathway in the inguinal white adipose tissue (iWAT) of HFD-fed mice. Importantly, deletion of adipose Sirt6 abolishes the effects of rifampicin on HFD-induced weight gain and obesity in mice. Our data collectively reveal that rifampicin alleviates diet-induced obesity by inducing Sirt6. These findings may support a novel approach to treat obesity.