Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion

Abstract The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3−/− (Shn3 −/− ) mice with augmented osteoblast activity, we show Shn3 −/− mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3 −/− mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.