LEPTIN-INDEPENDENT HYPERPHAGIA AND TYPE-2 DIABETES IN MICE WITH A MUTATED SEROTONIN 5-HT2C RECEPTOR GENE

Brain serotonin and leptin signaling contribute substantially to the r egulation of feeding and energy expenditure. Here we show that young a dult mice with a targeted mutation of the serotonin 5-HT2C receptor ge ne consume more food despite normal responses to exogenous leptin admi nistration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In additio n, older mice develop insulin resistance and impaired glucose toleranc e. Mutant mice also responded more to high-fat feeding, leading to hyp erglycemia without hyperlipidemia. These findings demonstrate a dissoc iation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predis pose to type 2 diabetes.