A Pivotal Role of Skeletal Tissues in the Regulation Mechanisms for Physiological Functions Mediated by Multiple Organ Networks

Abstract

Bone formation and maintenance are sophisticatedly orchestrated through a well-organized and highly regulated mechanism by two distinct cell types; bone-forming osteoblast and bone-resorbing osteoclast. It has been previously established that the adipocyte-derived hormone leptin regulates bone metabolism through the central nervous system and the sympathetic nervous system. We recently identified the osteoblast as the principal cell type in which the sympathetic tone could signal to regulate bone mass by generating and analyzing the cell specific adrenergic receptor deletion mice. The fact that adipocyte-derived hormone regulates bone metabolism implies that the skeleton might exert a feedback control of glucose metabolism. We then revealed that the skeleton acts as an endocrine regulator of energy metabolism through the osteoblast-specific secreted molecule osteocalcin that activates insulin secretion by pancreatic β-cells, insulin sensitivity in fat, liver, and muscle. Moreover, we have recently reported that the sympathetic tone into osteoblast is a pivotal mediator of leptin regulation of insulin secretion by regulating osteocalcin bioactivity. This unexpected functional cross talk between fat, nervous systems, and skeleton illustrates the importance of the skeleton for the regulation of major physiological functions such as glucose homeostasis in vertebrates.