Integrative physiology: defined novel metabolic roles of osteocalcin

Abstract

The prevailing model of osteology is that bones constantly undergo a remodeling process, and that the differentiation and functions of osteoblasts are partially regulated by leptin through different central hypothalamic pathways. The finding that bone remodeling is regulated by leptin suggested possible endocrinal effects of bones on energy metabolism. Recently, a reciprocal relationship between bones and energy metabolism was determined whereby leptin influences osteoblast functions and, in turn, the osteoblast-derived protein osteocalcin influences energy metabolism. The metabolic effects of bones are caused by the release of osteocalcin into the circulation in an uncarboxylated form due to incomplete gamma-carboxylation. In this regard, the Esp gene encoding osteotesticular protein tyrosine phosphatase is particularly interesting because it may regulate gamma-carboxylation of osteocalcin. Novel metabolic roles of osteocalcin have been identified, including increased insulin secretion and sensitivity, increased energy expenditure, fat mass reduction, and mitochondrial proliferation and functional enhancement. To date, only a positive correlation between osteocalcin and energy metabolism in humans has been detected, leaving causal effects unresolved. Further research topics include: identification of the osteocalcin receptor; the nature of osteocalcin regulation in other pathways regulating metabolism; crosstalk between nutrition, osteocalcin, and energy metabolism; and potential applications in the treatment of metabolic diseases.

Keywords: Bone Remodeling; Energy Metabolism; Leptin; Osteocalcin; Protein Tyrosine Phosphatases.

Fig. 1

Bimodal effects of leptin on osteoclast differentiation through hypothalamic sympathetic signaling and CART CART, Cocaine Amphetamine Regulated Transcript; RANKL, Receptor Activator for Nuclear Factor κB Ligand; ATF4, Activating Transcription Factor 4; β Adrb2, Beta Adrenergic receptor 2.

Fig. 2

Increased [OC_uc] in Esp knockout mice exerts physiological effects on fat, pancreas, and mitochondria to induce various metabolic enhancements. Ost-Ptp, Osteotesticular Protein Tyrosine Phosphatase; [OC_uc], blood concentration of uncarboxylated osteocalcin; Mt, Mitochondrial.