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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045548-11
Application #
7810603
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
1998-04-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
11
Fiscal Year
2010
Total Cost
$491,020
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Mera, Paula; Laue, Kathrin; Wei, Jianwen et al. (2016) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5:1042-7
Mera, Paula; Laue, Kathrin; Ferron, Mathieu et al. (2016) Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Cell Metab 23:1078-1092
Wei, Jianwen; Shimazu, Junko; Makinistoglu, Munevver P et al. (2015) Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell 161:1576-1591
Wei, Jianwen; Karsenty, Gerard (2015) An overview of the metabolic functions of osteocalcin. Rev Endocr Metab Disord 16:93-8
Ferron, Mathieu; Lacombe, Julie; Germain, Amélie et al. (2015) GGCX and VKORC1 inhibit osteocalcin endocrine functions. J Cell Biol 208:761-76
Wei, Jianwen; Flaherty, Stephen; Karsenty, Gerard (2015) Searching for additional endocrine functions of the skeleton: genetic approaches and implications for therapeutics. Expert Rev Endocrinol Metab 10:413-424
Swanson, Christine M; Shea, Steven A; Stone, Katie L et al. (2015) Obstructive sleep apnea and metabolic bone disease: insights into the relationship between bone and sleep. J Bone Miner Res 30:199-211
Wei, Jianwen; Hanna, Timothy; Suda, Nina et al. (2014) Osteocalcin promotes ?-cell proliferation during development and adulthood through Gprc6a. Diabetes 63:1021-31
Karsenty, Gerard; Oury, Franck (2014) Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 382:521-526
Obri, Arnaud; Makinistoglu, Munevver Parla; Zhang, Hong et al. (2014) HDAC4 integrates PTH and sympathetic signaling in osteoblasts. J Cell Biol 205:771-80

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