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-HT 2C 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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We thank N. Sall for animal colony supervision and genotyping; D. Yamashiro for assistance with the generation of growth curves; S. Akana for assistance with tissue collections; M. Heiman (Eli Lilly & Co.) for recombinant mouse leptin; A. Dorison for editorial assistance; and K. Feingold, C. Grunfeld and M. German for critical reading of the manuscript. Supported by NIDA, EJLB and NARSAD (L.H.T.) and NIDDK (A.M.S., M.F.D.).
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Nonogaki, K., Strack, A., Dallman, M. et al. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4, 1152–1156 (1998). https://doi.org/10.1038/2647
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