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Article
Nature Medicine  4, 1152 - 1156 (1998)
doi:10.1038/2647

Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene

Katsunori Nonogaki1, Alison M. Strack2, 3, Mary F. Dallman2 & Laurence H. Tecott1

1  Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California at San Francisco, San Francisco, California 94143-0984, USA

2  Department of Physiology, University of California at San Francisco, San Francisco, California 94143-0444, USA

3  Present address: Merck Research Laboratories, Merck & Co., PO Box 2000, RY80Y-145, Rahway, New Jersey 07065

Correspondence should be addressed to Laurence H. Tecott email:tecott@itsa.ucsf.edu
Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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