Schisantherin A interacts with gut bacteria to stimulate adipose tissue thermogenesis in obese mice via a TGR5‒p-CREB‒STAT6 signaling pathway.

The global epidemic of obesity challenges the scientific and medical communities to find different treatments. Schisantherin A (Sin A), a natural compound isolated from Schisandra chinensis (Turcz.), reduces the abundance of bile salt hydrolase-producing gut bacteria in obese mice, leading to accumulation of specific conjugated bile acids (CBAs). These elevated CBAs activate a signaling axis containing Takeda G protein-coupled receptor 5, phosphorylated cAMP-responsive element binding protein 1, and signal transducer and activator of transcription 6 (TGR5-p-CREB-STAT6), wherein CREB directly binds to the STAT6 promoter. Sin A-induced STAT6 activation promoted M2-like macrophages polarization to secret slit guidance ligand 3 (SLIT3), which consequently stimulated norepinephrine release in sympathetic neurons and induced thermogenesis in adipose tissue. This study thus identifies a pathway by which Sin A interacts with gut bacteria to stimulate CBA-mediated beiging of white adipose tissue, highlighting a promising natural product-based strategy for obesity treatment.