Review
Regulation of energy metabolism by the skeleton: Osteocalcin and beyond

https://doi.org/10.1016/j.abb.2014.05.022Get rights and content

Highlights

  • Bone was recently identified as an endocrine organ regulating glucose and energy metabolism.

  • Osteocalcin is a bone-derived hormone which affect glucose metabolism by regulating insulin secretion and sensitivity.

  • Osteocalcin is under the control of hormones implicated in energy metabolism.

  • Human cross-sectional studies largely confirmed the findings made in mice.

Abstract

The skeleton has recently emerged as an endocrine organ implicated in the regulation of glucose and energy metabolism. This function of bone is mediated, at least in part, by osteocalcin, an osteoblast-derived protein acting as a hormone stimulating insulin sensitivity, insulin secretion and energy expenditure. Osteocalcin secretion and bioactivity is in turn regulated by several hormonal cues including insulin, leptin, the sympathetic nervous system and glucocorticoids. Recent findings support the notion that osteocalcin functions and regulations are conserved between mice and humans. Moreover, studies in mice suggest that osteocalcin could represent a viable therapeutic approach for the treatment of obesity and insulin resistance. In this review, we summarize the current knowledge on osteocalcin functions, its various modes of action and the mechanisms implicated in the control of this hormone.

Introduction

Traditionally, bone has been viewed as a relatively static tissue, as a mere collection of calcified tubes only serving as a scaffold for other organs. In the past decade however a more complex picture of bone physiology has emerged. It is now clear that bone integrity and normal function depends upon, but also affects, other organs. For instance it is now known that bone plays a role in the maintenance of the hematopoietic stem cell niche, in the control of serum calcium and in the control of phosphate absorption by the kidney [1], [2], [3].

Presumably bone remodeling, the normal biological process by which bone tissue is constantly destroyed by osteoclasts and renewed by osteoblasts, is energetically costly for the rest of the body. Therefore, one can assume that bone remodeling is highly dependent on the energetic status of the organism. This view is supported by specific clinical observations. For example, anorexia nervosa and insulin-dependent diabetes mellitus are associated with osteoporosis, while a higher body mass index (BMI)1 is generally associated with increased bone mass [4], [5], [6], [7], [8]. Together, these observations suggested the existence of a coordinated endocrine regulation of bone and energy metabolism. In other words, that one can expect to identify hormones or circulating factors controlling both bone and energy metabolism [9]. Over the past ten years, several such hormones have been implicated in the control of bone remodeling. Those include leptin and adiponectin, two adipocyte-derived hormones implicated in the regulation of food intake and energy metabolism that also regulate bone mass [10], [11]. Additionally, gut-derived hormones such as glucagon-like peptides 1 and 2 and serotonin have been shown to regulate both bone remodeling and energy homeostasis [12], [13], [14], [15].

The demonstration of an endocrine control of bone mass by hormones otherwise implicated in the regulation of energy balance, combined with the general principle of endocrine feedback loops, raised an even more intriguing hypothesis, which is that bone cells themselves might secrete hormone(s) implicated in the regulation of glucose metabolism. This hypothesis led to the demonstration a few years ago that osteocalcin, an osteoblast-derived protein, was a hormone regulating glucose and energy homeostasis [16]. Since this initial discovery, several studies have expended and broaden our understanding of osteocalcin biology and more generally of bone as an endocrine organ. We will review here the most recent findings in mice and humans on the influence of bone on energy metabolism and the physiological regulation of bone endocrine function by intrinsic mechanisms and by hormonal signals. We will also try to integrate this knowledge into a unified model of osteocalcin regulation and action (Fig. 2, Fig. 3).

Section snippets

Osteocalcin: a bone-derived hormone regulating energy metabolism

Osteocalcin is a small protein (46 a.a. in mouse and 49 a.a. in human) produced by bone and posttranslationally modified on specific glutamic acid (GLU) residues that are carboxylated to form γ-carboxyglutamic acid (GLA) residues (Fig. 1). Although this modification is usually associated with increased affinity for mineral ions, both loss- and gain-of-function in vivo experiments have failed to demonstrate a critical function for osteocalcin in extracellular matrix mineralization, at least in

Regulation of osteocalcin activity

The emerging biological importance of osteocalcin begs the question of the regulation of its activity. Before it is secreted by osteoblasts, osteocalcin is γ-carboxylated on GLU 13, 17 and 20 in mouse, and on GLU 17, 21 and 24 in human [43] (Fig. 1A). γ-Carboxylation of osteocalcin and other so called GLA proteins occurs in the lumen of the endoplasmic reticulum and involves two enzymes, γ-glutamyl carboxylase (γ-carboxylase) and vitamin K epoxide reductase (VKORC1), which together constitute

Osteocalcin action and regulation in humans

Since the original identification of the metabolic function of osteocalcin in mice, several cross-sectional and observational studies have addressed the role of osteocalcin in glucose and energy metabolism in humans. A systematic survey of the literature published between 2007 and 2014 allowed us to identify a total of 82 studies addressing a link between osteocalcin and metabolic markers or anomalies in humans (see Table 1 for details). The vast majority of those studies confirmed the findings

Therapeutic potential of osteocalcin

Type 2 diabetes is a disease characterized by obesity, insulin resistance and β-cell dysfunction. Since osteocalcin has the capacity to modulate several of the factors contributing to this disease, we can presume that osteocalcin could be used as a valuable treatment for diabetes or at least to slow down the progression of this disease. Several studies support the therapeutic potential of osteocalcin.

Both type 1 and type 2 diabetes are characterized by a loss of β-cells leading to their

Osteocalcin-independent endocrine function of bone in energy metabolism

Although osteocalcin appears to be a major mediator of bone endocrine functions, recent findings suggest the existence of additional bone-derived factors implicated in the control of glucose metabolism. For instance, it was observed that partial ablation of osteoblasts in adult mice results in decreased glucose tolerance, hypoinsulinemia and decreased insulin sensitivity, similarly to the phenotype observed in osteocalcin-deficient mice [94]. However, unlike what was observed in absence of

Conclusions

Being the most abundant non-collagenous bone protein, it was unexpected to discover that osteocalcin does not overtly affect bone development or structure and that instead it acts as a hormone affecting glucose metabolism as well as male reproduction and brain development [98]. Since osteocalcin receptor, GPRC6A, is expressed in tissues unrelated to these functions, we can indeed speculate that osteocalcin might have additional biological activities beyond what has already been described.

Acknowledgments

This work was supported by the Canada Research Chair in Bone and Energy Metabolism (M.F.) and by the Canadian Institutes of Health Research (M.F.).

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