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

Abstract

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 (γ/) 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, γ mice exhibit more bone density, structure, and strength by uncoupling bone formation from resorption. When challenged with a high-fat diet, γ 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.

Energy Metabolism in the Bone is Associated with Histomorphometric Changes in Rats with Hyperthyroidism

“…These results indicate that ATP synthesis and glucose catabolism were considerably increased in the femoral tissues of the hyperthyroid rats. It has previously been found that bones play an essential role in whole-body glucose homeostasis, and bone remodelling is a dynamic ATP-consuming process that occurs via glucose catabolism [20-23]. T4 has been shown to accelerate the rates of oxygen consumption and heat production in various body tissues [7].…”

Bone: Another potential target to treat, prevent and predict diabetes

“…Subsequently, the question of which molecules link bone and glucose metabolism arises. Mouse studies have revealed that several osteokines, such as OCN, LCN2, BMP7 and sclerostin, actively participate in energy metabolism by modulation of glucose homeostasis, appetite and browning of adipose tissue. Meanwhile, the possible involvement of RANKL and NPY cannot be neglected.…”

“…Osteocytes are the terminally differentiated osteoblasts and comprise nearly 95% of the cells residing in bone . Generally recognized as mechanical load‐sensing effectors, osteocytes are now known for their indispensable role in decreasing body weight upon increased loading and in mediating energy metabolism through secretory factors …”

“…With the deletion of Pparγ in osteocytes ( Pparγ ocy −/− ), a series of improved metabolic phenotypes, including browning of WAT and enhanced energy expenditure, were observed . Correspondingly, Pparγ ocy −/− mice, regardless of having a normal chow diet or a high‐fat diet, demonstrated improved glucose tolerance and insulin sensitivity compared with Pparγ oc y +/+ mice .…”

“…Recently, a second osteokine, lipocalin2 (LCN2), was discovered; it regulates appetite through its action on the hypothalamus . In addition to osteoblasts, osteocytes, the most abundant cells in bone matrix, have been suggested to act on the browning of white adipose tissue (WAT) and on energy expenditure through secretion of bone morphogenetic protein 7 (BMP7) and sclerostin . The implication of bone resorption in glucose homeostasis has also been examined .…”