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 the molecular links between osteoblast function and systemic energy metabolism remain unclear. Here, we utilized Schnurri-3^−/− (Shn3^−/−) mice with augmented osteoblast activity, to probe the general relationship between bone formation and metabolic syndrome. Shn3^−/− mice display resistance against high-fat diet-induced obesity with improved glucose homeostasis and insulin sensitivity associated with enhanced browning of white adipose tissue (WAT). Conditional deletion of Shn3 in osteoblasts (Shn3^Osx mice) but not adipocytes (Shn3^Adipoq mice) recapitulates the obesity resistance phenotype seen in Shn3^−/− mice, indicating that this phenotype is driven by the skeleton. Through in vitro co-culture and in vivo fat-pad transplantation assays, we demonstrate that cytokines secreted by activated osteoblasts lacking Shn3 expression promote WAT browning. Among them, we identify SLIT2 as a Shn3-regulated factor secreted by osteoblasts that regulates WAT browning, with osteoblasts serving as the major source of systemic circulating SLIT2. Lastly, AAV-mediated silencing of Shn3 phenocopied the lean phenotype and augmented glucose metabolism in Shn3-deficient mice. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated production of SLIT2 in osteoblasts, offering a therapeutic target with the potential to address both bone loss and metabolic syndrome.