Bone and the regulation of global energy balance

Abstract

The skeleton, populated by large numbers of osteoblasts and long-lived osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition and mineralization of bone matrix during bone modelling and remodelling. When these energetic demands are not met, bone acquisition is suppressed. Recent findings suggest that key developmental signals emanating from Wnt low-density lipoprotein-related receptor 5 and hypoxia-inducible factor pathways impact osteoblast bioenergetics to accommodate the energy requirements for bone cells to fulfil their function. In vivo studies in several mutant mouse strains have confirmed a link between bone cells and global metabolism, ultimately leading to the identification of hormonal interactions between the skeleton and other tissues. The hormones insulin and leptin affect postnatal bone acquisition, whilst osteocalcin produced by the osteoblast in turn stimulates insulin secretion by the pancreas. These observations have prompted additional questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve management of affected patients. In this review, we highlight recent studies in this field and offer a perspective on the evolutionary implications of bone as a metabolic endocrine organ.

Keywords: genetic mouse models; insulin; leptin; osteoblasts.

Fig. 1

Metabolic flexibility of osteoblasts. Much remains to be learned about the metabolic requirements of bone-forming osteoblast. Firstly (A), insulin and insulin receptor (IR) signaling stimulates the glucose transporter (Glut)4-mediated uptake of glucose, which can be utilized via oxidative phosphorylation (Ox.Phos) or aerobic glycolysis. Secondly (B), the Low-density lipoprotein receptor (LDLR) facilitates the uptake of a significant fraction of postprandial lipoproteins (LDL) by bone. Free fatty acids and triglycerides that can then be oxidized to generate ATP. Our recent findings suggest that activation of the Frizzled (Fz)-Lrp5 signaling complex by Wnt-ligands favors lipid oxidation in the osteoblast.

Fig. 2

Osteoblast differentiation and osteocalcin activation in response to insulin. The activation of the insulin receptor (IR) expressed by osteoblasts stimulates both osteoblast differentiation and the activation of the hormone osteocalcin. By triggering the downregulation of Twist2, insulin signaling relieves suppression on the transcription factor Runx2, required for osteoblast differentiation. Once activated, undercarboxylated osteocalcin stimulates proliferation and insulin secretion by the pancreatic β-cell and increases insulin sensitivity in adipocytes and other target cells for insulin. Red lines indicate inhibitory interactions. Green arrows indicate activating interactions.