Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice

Abstract

The osteoblast-specific secreted molecule osteocalcin behaves as a hormone regulating glucose metabolism and fat mass in two mutant mouse strains. Here, we ask two questions: is the action of osteocalcin on ␤ cells and adipocytes elicited by the same concentrations of the molecule, and more importantly, does osteocalcin regulate energy metabolism in WT mice? Cell-based assays using isolated pancreatic islets, a ␤ cell line, and primary adipocytes showed that picomolar amounts of osteocalcin are sufficient to regulate the expression of the insulin genes and ␤ cell proliferation markers, whereas nanomolar amounts affect adiponectin and Pgc1␣ expression in white and brown adipocytes, respectively. In vivo the same difference exists in osteocalcin's ability to regulate glucose metabolism on the one hand and affect insulin sensitivity and fat mass on the other hand. Furthermore, we show that long-term treatment of WT mice with osteocalcin can significantly weaken the deleterious effect on body mass and glucose metabolism of gold thioglucose-induced hyperphagia and high-fat diet. These results establish in WT mice the importance of this novel molecular player in the regulation of glucose metabolism and fat mass and suggest that osteocalcin may be of value in the treatment of metabolic diseases.fat ͉ insulin ͉ diet-induced obesity ͉ diet-induced diabetes ͉ adiponectin W e recently showed that the uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin functions as a hormone regulating glucose metabolism and fat mass (1). However, this unexpected role for osteocalcin had not previously been exclusively demonstrated in genetically modified animals such as the Osteocalcin Ϫ/Ϫ and Esp Ϫ/Ϫ mice (1, 2). The latter mouse model exhibits an osteocalcin gain of bioactivity. Data generated in these two animal models and cell-based assays showed that osteocalcin can increase ␤ cell proliferation, stimulate insulin expression and secretion by pancreatic ␤ cells, enhance energy expenditure, and increase expression of adiponectin, an insulin-sensitizing hormone produced by adipocytes (3, 4).The next critical question to answer is whether the functions of osteocalcin on energy metabolism extend to WT animals. Moreover, if it is the case, one needs to know whether identical or different concentrations of osteocalcin are required to affect glucose metabolism and fat mass. Answers to these questions are of critical importance for two reasons. First, if osteocalcin has an effect in WT mice it would firmly establish the notion that it is a physiologically important hormone; second, it would start addressing the therapeutic potential of this new player in the regulation of energy metabolism.Thus, we embarked on a systematic analysis of osteocalcin relevance in regulating energy metabolism in WT mice. We performed in vitro and in vivo assays to determine the doses of osteocalcin able to affect various aspects of energy metabolism and tested different doses of osteocalcin in WT mice fed either a normal diet or a diet favo...

Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification

“…Polymorphisms may not be able to reflect the status of posttranslational modification (g-carboxylation) that appears to be the mechanism by which OC bioactivity is regulated. (16,18) In corroboration of other studies, (41,42) OC levels (total and carboxylated) were significantly correlated with bone mass, and women with high OC levels had lowest TB BMD. Serum OC also predicted fracture risk independent of weight and bone mass.…”

“…(16,17) Another study done in wild-type mice also observed the importance of osteocalcin in the regulation of glucose metabolism and fat mass. (18) At its simplest level, this relationship offers a plausible link between the established inverse relationship between body size, osteoporosis, and fracture risk.…”

The osteoblast: An insulin target cell controlling glucose homeostasis

“…It is this undercarboxylated form of osteocalcin that appears to function as a hormone and alter pancreatic b-cell proliferation, insulin expression, insulin secretion, insulin sensitivity, and energy PERSPECTIVE J JBMR expenditure. (5,6) In accordance with this concept, treatment of wild-type mice with warfarin decreased blood glucose levels. (7) In an unexpected turn of events, the osteoblast was found to express the Esp gene, which encodes a protein tyrosine phosphatase that hampers glucose metabolism by inhibiting osteocalcin endocrine functions.…”

Gene expression profile in bone of diabetes-prone BB/OK rats fed a high-fat diet

“…Now it is well-accepted that the skeleton is an endocrine organ that, through the secreted molecule osteocalcin (Bgla), favors insulin secretion by insulin-producing b cells and insulin sensitivity in liver, muscle, and adipocytes (Ferron et al 2008;Fukumoto and Martin 2009;Hinoi et al 2008;Lee et al 2007;Lee 2010;Lieben et al 2009;Schwetz et al 2012). The protein osteocalcin is produced by osteoblasts and odontoblasts and has been known as a marker of bone turnover (Brown et al 1984;Ducy 2011).…”