The pathobiochemical bases controlling bone formation in physiologic situations and disease states are not known. This is a biochemical question of critical importance since osteoporosis, a low bone mass disease characterized by a relative decrease of bone formation, is the most prevalent disease in developed countries. Dr. Karsenty and his lab have recently demonstrated that leptin is a powerful inhibitor of bone formation whose absence leads to a high bone mass phenotype even in ovariectomized animals and those with increased circulating glucocorticosteroids. This latter result indicates that leptin may be the most powerful regulator of bone formation identified to date, as it is the only regulatory pathway that can overcome the deleterious consequences of hypogonadism and hypercorticosteroidism on bone mass. Lastly, Dr. Karsenty has shown that leptin must bind to its hypothalamic receptor, not to the osteoblast, to exert its regulatory role on bone formation, thus uncovering that bone formation is a central function. Dr. Karsenty and his lab intend in this application to explore the molecular bases of leptin action on bone formation. They believe that this project may lead to the design of novel therapeutics enhancing bone formation for osteoporosis.
The specific aims of this application are: 1. To compare the potency of leptin in controlling bone mass and body weight and the relative efficiency of peripheral versus central delivery of leptin in the control of bone formation. 2. To determine whether a naturally occurring soluble (decoy) form of the leptin receptor can prevent leptin inhibitory action on bone formation. 3. To determine whether or not leptin affects bone formation by acting on early osteoblast progenitors. 4. To determine whether leptin uses a pituitary or a neuronal pathway to regulate bone formation. 5. To identify the hypothalamic nuclei that are involved in the regulation of bone formation by leptin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058883-03
Application #
6635338
Study Section
General Medicine B Study Section (GMB)
Program Officer
Malozowski, Saul N
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$376,467
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Kajimura, Daisuke; Lee, Ha Won; Riley, Kyle J et al. (2013) Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab 17:901-15
Karsenty, Gerard (2012) The mutual dependence between bone and gonads. J Endocrinol 213:107-14
Kajimura, Daisuke; Hinoi, Eiichi; Ferron, Mathieu et al. (2011) Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J Exp Med 208:841-51
Shi, Yu; Oury, Franck; Yadav, Vijay K et al. (2010) Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab 11:231-8
Yadav, Vijay K; Oury, Franck; Suda, Nina et al. (2009) A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138:976-89
Shi, Yu; Yadav, Vijay K; Suda, Nina et al. (2008) Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci U S A 105:20529-33
Elefteriou, Florent (2008) Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 473:231-6
Singh, Manvendra K; Elefteriou, Florent; Karsenty, Gerard (2008) Cocaine and amphetamine-regulated transcript may regulate bone remodeling as a circulating molecule. Endocrinology 149:3933-41
Ahn, Jong Deok; Dubern, Beatrice; Lubrano-Berthelier, Cecile et al. (2006) Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology 147:3196-202
Dacquin, Romain; Davey, Rachel A; Laplace, Catherine et al. (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164:509-14

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