Faculty & Staff
Doctoral Training and Teaching Faculty
Gerard Karsenty, M.D., Ph.D.
Professor and Chair, Genetics and Development
Department of Genetics and Development
Department of Medicine
701 West 168th Street Room 1602A New York NY 10032
M.D., Ph.D. 1984, University of Paris V
Postdoctoral Fellowship 1987, National Institute of Health
Postdoctoral Fellowship 1990, University of Texas M.D. Anderson Cancer Center
The lab aims at using mouse genetics to identify novel functional connections between organs and new physiologies that are relevant to human. The overarching assumption explaining all the projects currently ongoing in the laboratory is that there are many new physiological pathways to be discovered in mammals. Our aim is not so much to identify novel regulatory molecules involved in known functions but rather to identify, study and elucidate molecularly totally novel functions or made of regulation for various organs. To test this hypothesis we use skeleton as an organ and the mouse as a model organism.
Based on an evolutionary and clinically-based view of bone modeling and remodeling, the physiological functions whereby bone tissue is constantly renewed we hypothesize that there must be a common endocrine control of bone mass and energy metabolism. In keeping with the logic of this hypothesis the hormone(s) responsible for this co-regulation should appear during evolution with bone because it is precisely the energetic needs of this tissue that justifies its existence. Leptin fulfills these criteria and it inhibits both appetite and bone mass accrual. Over the last 8 years we have delineated the road map of leptin in the brain and identified the major signaling pathways linking leptin signaling in the brain to bone cells in the periphery. Current studies in this founding project aim at unraveling the signal transduction pathway occurring in leptin target neurons in the brain.
Identifying a link, even indirect, between fat cells and bone mass begged the question to know if bone cells were exerting a feedback regulation on adipocytes and any aspect of energy metabolism. In other words we asked whether bone was an endocrine organ. Testing this hypothesis allowed us to identify a bone-specific hormone called osteocalcin whose functions are to increase insulin secretion and sensitivity. Right now numerous studies address in the lab at the molecular level the mechanism of action of osteocalcin in target cells as well as other aspects of its biology. Those include but are not limited to the identification of its receptor and of extracellular regulators of activity.
In another line of research the molecular elucidation of two known human genetic diseases allowed us to identify another novel physiological loop this one linking bone and the GI tract. Indeed, we have shown recently that gut-derived serotonin is a hormone whose main function is to inhibit bone formation by osteoblast. Because we have elucidated the entire molecular cascade from the synthesis of the hormone to its target genes in osteoblast we are now in a position to test the therapeutic relevance of this pathway in the treatment of osteoporosis. This work on serotonin has triggered a more general interest in the lab about the possible role and mechanism of action of brain-derived serotonin in the control of bone mass. These projects focused on serotonin regulation of bone mass and address both basic physiological functions and its potential therapeutic outcome in humans.
Recent Publications - Pubmed
Yadav VK, Oury F, Suda N, Liu Z-W, Gao X-B, Confavreux C, Klemenhagen CK, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Horvath TL and Karsenty G. : (2009) A serotonin-dependent mechanism explains leptin regulation of bone mass, appetite and energy expenditure . Cell 138(5): 976-989
Yadav VK, Ryu JH, Suda N, Tanaka K, Gingrich J, Schutz G, Glorieux FH, Insogna K, Mann JJ, Hen R, Ducy P and Karsenty G: (2008) Lrp5 control bone mass by inhibiting serotonin synthesis in the duodenum. Cell 135(5): 825-837
Lee NK, Sowa H, Hinoi E, Ferron M Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee M, Jung, DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, and Karsenty G: (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130: 456-469