Role of the CNS in the Metabolic Syndrome

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DESCRIPTION (provided by applicant): The prevalence of overweight children in the US has increased by more than 50% in the last 10 years. Body weight is tightly regulated through a negative endocrine feedback loop by communication of signals from adipose tissue to the CMS. The major health consequence of obesity is metabolic syndrome, defined as abdominal obesity, dyslipidemia, hypertension (HTN), and impaired glucose tolerance (IGT). Hypothalamic circuits are involved in the regulation of all of these traits. We hypothesize that CMS resistance to insulin and leptin leads; a) to increased food intake and obesity, and b) to traits of metabolic syndrome independent of the resultant obesity. The Zucker fatty rat (ZF) is a model of metabolic syndrome with obesity, HTN, dyslipidemia, and IGT. Our objective is to determine how insulin and leptin signaling in the hypothalamus regulates the traits of metabolic syndrome by determining when in post-partum development these traits occur. Next, using a gain-of-function approach we will determine if restoration of hypothalamic function can prevent the onset of a) adiposity and b) metabolic syndrome. Thus CNS resistance to insulin and leptin may be important in the development of obesity and metabolic syndrome in children and adolescents.