Obesity and its associated pathologies are a major health problem throughout the world. And in spite of years of focused research, two conclusions are inescapable. The first is that the health-care community has only ineffective treatments to offer, relegating obese individuals and their societies to a lifetime of psychological, medical and economic hardship. The second and more sobering is that the incidence of obesity continues to rise, the rate being accelerated in countries as they become economically more self-sufficient. One factor thought to contribute to this is a high level of dietary fat intake. The goal of Project 2, like that of the entire Program Project, is to begin defining the mechanisms underlying in a rigorous and systematic way the changes that occur in the body when a diet high in fat is consumed. The overall goal of Project 2 is to evaluate several hypotheses concerning the adiposity-related negative feedback signals that are critical in the regulatory process that governs adiposity. Specifically, I hypothesize that chronic consumption of a high-fat diet reduces the ability of the adiposity signals, insulin and leptin, to cross the blood-brain barrier, such that the brain receives an inaccurate (in fact, relatively reduced) signal regarding body fat content. I further hypothesize that chronic consumption of a high-fat diet lowers the sensitivity of the brain to leptin and insulin. There are three specific aims. 1) To evaluate the hypothesis that chronic consumption of high-fat diet reduces the sensitivity of the brain to intraventricularly (ivt) administered insulin and leptin. 2) To evaluate the hypothesis that chronic consumption of a high-fat diet reduces the insulin- and leptin-induced augmentation of cholecystokinin (CCK)-induced reduces of single-meal size. 3) To evaluate the hypothesis that the transport of insulin and leptin form plasma into the central nervous system (CNS) is compromised in animals fed a high-fat diet chronically.
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