The fact that an adipocyte-derived hormone like leptin regulates bone remodeling raises the project that bone cells may in turn influence adipocyte biology. While testing this hypothesis we identified a gene, Esp, encoding a tyrosine phosphatase whose osteoblast-specific deletion results in an increase in insulin and adiponectin secretion by pancreatic cells and adipocytes respectively. Looking for substrates of the Esp gene product we noted that Osteocalcin-deficient mice had a phenotype that is the mirror image of the one observed in Esp-deficient mice. Osteocalcin -/- mice display a decrease in insulin and in adiponectin secretion. Moreover, removing one allele of osteocalcin sufficed to correct the entire metabolic phenotype of the Esp -/- mice. Based on these and additional published preliminary data we have shown that osteocalcin is a hormone regulating insulin secretion and sensitivity we now intend to foster our molecular understanding of how osteocalcin regulates energy metabolism. To achieve this goal we propose the following specific aims: 1. To demonstrate that gamma carboxylase is a target of OST-PTP, the Esp gene product in vivo 2. To generate mice lacking, in osteoblasts only, the Vitamin K epoxy reductase C1, another enzyme involved in carboxylation of osteocalcin 3. To determine whether bones, through osteocalcin, are responsible of the increase in insulin secretion observed in absence of leptin 4. To define how insulin signaling in osteoblasts regulates osteocalcin expression or bioactivity.

Public Health Relevance

. Type 2 diabetes and obesity is a growing public concern. Here we identified a potential new hormone regulating glucose metabolism. This hormone may be an important therapeutic tool in the fight against the metabolic syndrome.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Karsenty, Gerard; Oury, Franck (2014) Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 382:521-6
Wei, Jianwen; Hanna, Timothy; Suda, Nina et al. (2014) Osteocalcin promotes *-cell proliferation during development and adulthood through Gprc6a. Diabetes 63:1021-31
Obri, Arnaud; Makinistoglu, Munevver Parla; Zhang, Hong et al. (2014) HDAC4 integrates PTH and sympathetic signaling in osteoblasts. J Cell Biol 205:771-80
Wei, Jianwen; Ferron, Mathieu; Clarke, Christopher J et al. (2014) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest 124:1-13
Bornstein, Sheila; Brown, Sue A; Le, Phuong T et al. (2014) FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice. Endocrinology 155:3516-26
Oury, Franck; Khrimian, Lori; Denny, Christine A et al. (2013) Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155:228-41
Lacombe, Julie; Karsenty, Gerard; Ferron, Mathieu (2013) In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice. Mol Metab 2:498-504
Ferron, Mathieu; McKee, Marc D; Levine, Robert L et al. (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50:568-75
Wei, Jianwen; Ducy, Patricia (2010) Co-dependence of bone and energy metabolisms. Arch Biochem Biophys 503:35-40
Ferron, Mathieu; Wei, Jianwen; Yoshizawa, Tatsuya et al. (2010) An ELISA-based method to quantify osteocalcin carboxylation in mice. Biochem Biophys Res Commun 397:691-6

Showing the most recent 10 out of 28 publications