Bone Regulates Browning and Energy Metabolism Through Mature Osteoblast/Osteocyte PPARγ Expression

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of energy metabolism. In bone, it is known to regulate osteoblast differentiation and osteoclast activity. Whether PPARγ expression in bone cells, particularly osteocytes, regulates energy metabolism remains unknown. Here, we show that mature osteoblast/osteocyte-specific ablation of PPARγ in mice (Ocy-PPARγ^-/^-) alters body composition with age, namely, to produce less fat and more lean mass, and enhances insulin sensitivity and energy expenditure compared with wild-type mice. In addition, Ocy-PPARγ^-/- mice exhibit more bone density, structure, and strength by uncoupling bone formation from resorption. When challenged with a high-fat diet, Ocy-PPARγ^-/- mice retain glycemic control, with increased browning of the adipose tissue, decreased gluconeogenesis, and less hepatic steatosis. Moreover, these metabolic effects, particularly an increase in fatty acid oxidation, cannot be explained by decarboxylated osteocalcin changes, suggesting existence of other osteokines that are under the control of PPARγ. We further identify bone morphogenetic protein 7 as one of them. Hence, osteocytes coregulate bone and glucose homeostasis through a PPARγ regulatory pathway, and its inhibition could be clinically relevant for the prevention of glucose metabolic disorders.