Updated project metadata. Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR (db/db) and leptin (ob/ob) are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4, a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO cite, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Surprisingly, exogenous ANGPTL4 treatment not only promoted HO, but facilitated the transformation from white to brown adipose tissue in mice. These findings identify ANGPTL4 as a novel ligand for LepR to stimulate HO and regulate fat metabolism.