Role of Osteoblasts in Regulation of Energy Metabolism

Abstract

Diseases of compromised glucose metabolism, such as type II diabetes, have been for years correlated with defects in bone mass or strength. However, a reverse regulation of energy homeostasis by the skeleton was not suspected until very recently. A series of genetic studies have demonstrated that the skeleton regulates glucose metabolism and energy expenditure in an endocrine manner. The bone-derived protein osteocalcin acts as a hormone that confers the signal of the osteoblasts to the peripheral tissues that regulate energy metabolism: pancreas, muscle, liver, and white adipose tissue. Osteocalcin favors β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. In addition, insulin signaling in osteoblasts is a positive regulator of osteocalcin production and activity, confirming the existence of a pancreas-bone feedback loop. At the molecular level, two transcription factors, the broadly expressed FoxO1 and the osteoblast-enriched ATF4, act in osteoblasts to regulate energy homeostasis by regulating the activity of osteocalcin. In addition to studies in rodents, a growing body of evidence in the clinical literature has confirmed a favorable link between osteocalcin and energy homeostasis, suggesting that the metabolic functions of the skeleton are retained in humans.