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Reciprocal Regulation of Bone and Energy Metabolism

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Remodeling allows bones to renew themselves and this process requires a fair amount of energy. In view of this, Lee and Karsenty hypothesized that there is somewhat of a common control of bone and energy metabolism. That started a search for a bone derived hormone that in turn regulates energy metabolism. The clinical observation that obesity protects from osteoporosis led to the proposal that bone remodeling was dependent, in some way, from an adipose tissue derived hormone, leptin. The researchers showed that leptin regulates bone mass. It binds to its receptor on hypothalamic neurons and then uses 2 pathways: (1) sympathetic signaling in osteoblasts which favors osteoclast differentiation by inducing RANKL gene expression, and (2) through CART (cocaine-and amphetamine-regulated transcript) inhibiting the RANKL expression in osteoblast (Figure 1). In view of these data they raised the question: is the skeleton, in turn, regulating any aspect of energy metabolism? This led to the search of a bone derived hormone.

Figure 1. Schematic representation of bone mass regulation by fat.
The adipocyte-derived hormone leptin binds to its receptor on hypothalamic neurons and then uses the sympathetic tone and cocaine- and amphetamine-regulated transcript (CART) to regulate bone function and RANKL expression in osteoblasts.

In search of that hormone, an osteocalcin-/- mouse was generated. It displayed a high bone mass phenotype and it also had an abnormal amount of visceral fat. This was the first evidence suggesting that skeleton regulates energy metabolism. Thereafter, mutant mice-lacking genes, expressed preferentially in osteoblast, were generated. The first gene of interest was Esp; it encodes a receptor like protein tyrosine phosphatase termed OST-PTP4. These mice had a surprising phenotype pointing towards new modes of regulation of glucose metabolism: increased insulin secretion with hypoglycemia, increase in beta cell proliferation, and an increase in insulin sensitivity. Given the increase in insulin sensitivity, the mutants should be fatter. Instead they had less fat because of an increase in energy expenditure; furthermore appetite was not affected. In addition, mice overexpressing Esp only in osteoblasts developed type 2 diabetes phenotype on a normal diet.

Osteocalcin was shown to be the molecule made by osteoblasts that accounts for the osteoblast-mediated regulation of gene expression of insulin in islets and of adiponectin, an insulin-sensitizing adipokine in adipocytes. It then appears that the Esp-deficient mice metabolic phenotype is caused by a gain of osteocalcin bioactivity and that OST-PTP regulates indirectly osteocalcin’s post-translational modifications; it favors the carboxylation of osteocalcin to transform it into bone gla protein. A small portion of non carboxylated osteocalcin is circulating and has the ability to improve glucose handling as described (Figure 2).

Figure 2. Osteocalcin in its uncarboxylated form is an osteoblast-derived hormone that improves glucose handling.
OST-PTP, the Esp gene product, favors, through yet unknown mechanisms, the carboxylation of osteocalcin. In the absence of Esp, more osteocalcin is uncarboxylated. This uncarboxylated form of osteocalcin increases expression of the insulin gene in b cells and the expression of the adiponectin gene in adipocytes, resulting in an increase in insulin secretion and in insulin sensitivity, respectively.

The authors further evaluated the potential relevance of these findings. They interpreted a series of experiments concluding that the increase in insulin sensitivity might protect from diabetes in a situation in which insulin secretion is low but not absent.
Lee NK, Karsently G. Reciprocal regulation of bone and energy metabolism. Trend Endocrinol Metab. 2008;19:161-166.

Editor’s Comment

In recent years this provocative work has attracted great attention. It shows that communication from metabolism to bone is not unidirectional and that bone regulates glucose metabolism and fat mass via the uncarboxylated form of osteocalcin in a complex crosstalk.¹ Therefore it is of interest that the association between serum osteocalcin concentration and markers of dysmetabolic phenotype was evaluated in a group of adults.² It was shown that serum osteocalcin was inversely associated with blood markers of dysmetabolic condition and measures of obesity. These findings need to be replicated to further test the initial hypothesis and to be extended to further studies in relation to type 2 diabetes. There is presently a major interest in this new presentation of energy metabolism including bone as a major actor.

Raphaël Rappaport, MD

References - (linked to )

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Last Updated: 2/2/2011