GENETIC APPROACHES TO SEROTONIN AND FEEDING BEHAVIOR

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DESCRIPTION: (Adapted from the Investigator's Abstract) Brain serotonin systems are strongly implicated in the regulation of normal feeding behavior and in the dysregulation of feeding observed in eating disorders. Several lines of evidence indicate that serotonin 5-HT2C receptor subtype contributes significantly to the serotonergic inhibition of food intake. Consistent with this, mice lacking functional setotonin 5-HT2C receptors display reduced sensitivity to appetite suppressant drugs that act through serotonin systems. In addition, these animals exhibit a dysregulation of feeding behavior leading to chronic elevations of food intake, late-onset ('middle-age") obesity and enhanced susceptibility to type 2 diabetes. Several features of this obesity syndrome are reminiscent of common forms of the human condition. It is proposed that 5-HT2C receptor mutants provide a unique genetic model in which obesity results from a primary defect in feeding behavior rather than a direct effect of the mutation on energy expenditure. In addition to testing this hypothesis, the neural mechanisms through which 5-HT2C receptors regulate feeding will be explored. In Aim 1, detailed studies of feeding behavior will be performed to test the hypothesis that 5-HT2C receptor mutants compensate for their overeating by increasing energy expenditure and that subsequent obesity results from an age dependent failure to maintain this compensation. In aim 3, mechanisms through which serotonin systems compensate for the 5-HT2C receptor mutation will be explored. Particular attention will be paid to potential compensation by the 5-HT1B receptor, including studies of feeding behavior and energy balance in "double-mutant" mice lacking both the 5-HT2C and 5-HT1B receptor subtypes. Studies of Aim 4 will identify brain regions and transmitter systems through which 5-HT2C receptors may regulate feeding. Hypotheses generated from the results of aim 4 will be tested in Aim 5 through the development of mice in which 5-HT2C receptor mutations are localized to restricted brain regions and cell types.