This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 149/3/955    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Wade, J. M. Articles by Goulding, E. H. PubMed PubMed Citation Articles by Wade, J. M. Articles by Goulding, E. H.

Synergistic Impairment of Glucose Homeostasis in ob/ob Mice Lacking Functional Serotonin 2C Receptors

Department of Psychiatry (J.M.W., P.J., A.W.M., L.H.T., E.H.G.), University of California, San Francisco, San Francisco, California 94158; and Department of Nutrition (J.G., P.J.H.), University of California, Davis, Davis, California 95616

Address all correspondence and requests for reprints to: Laurence H. Tecott, Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158. E-mail: larry.tecott{at}ucsf.edu.

To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals’ diabetes phenotype would not have been predicted from the phenotypic characterization of mice bearing mutations of either the leptin (OB mutant mice) or the serotonin 2C receptor gene (2C mutant mice). The synergistic impairment in glucose homeostasis developed at an age when OB2C mice did not differ in body weight from OB mice, suggesting that this impairment was not an indirect consequence of increased adiposity. We also demonstrated that the improvement in glucose tolerance in wild-type mice treated with the serotonin releaser and reuptake inhibitor fenfluramine was blunted in 2C mutant mice. These pharmacological and genetic findings provide evidence that the serotonin 2C receptor has direct effects on glucose homeostasis.