The objective of this proposal is to explore the role of nutrition, insulin and insulin-like growth factor II (IGF-II) in the onset of obesity. Recently, IGF-II has been shown to decrease food intake and body weight when injected intracerebroventricularly (icv) in free feeding rats. Further, concentrations of IGF-II in specific brain areas change response to a meal. Both nutrition and insulin have profound effects on peripheral IGF-II concentrations and receptor binding and therefore may affect brain IGF-II metabolism as well. The planned experiments are designed to determine (1) whether insulin and/or nutrition act to alter IGF-II function in the brain (2) the mechanism for these changes (3) what role these changes play in insulin or nutrition induced obesity. IGF-II peptide concentrations and receptor binding will be measured in specific regions of the brain after infusion of insulin or the feeding of obesity inducing diets. Where brain IGF-II concentrations are altered, mRNA levels will be determined as an index of turnover. A regional approach should illumine differences that could be obscured by analyses of larger brain areas. In Part I, the acute effects of insulin on IGF-II metabolism in the brain will be examined. In Part II, the effect of chronic hyperinsulinemia on brain IGF-II function will be assessed. This will be done by central and peripheral infusion of insulin as well as by nutritional manipulation. Rats will be fed diets that induce obesity with and without accompanying hyperinsulinemia and the affects of these diets on IGF-II metabolism will be determined. In contrast, rats resistant to dietary induced obesity will also be examined. Animal models of obesity will be characterized for IGF-II and compared to lean littermates. In Part III, animals that are obese and/or hyperinsulinemic will be examined before and after a meal challenge and compared with regard to brain IGF-II metabolic changes which occur following a meal. Such a comparison could help illustrate pathways involved in the onset of obesity. Collectively the proposed studies will provide important physiological data on the brain changes which occur in obese individuals. Such information could lead to a better understanding of body weight regulation and the etiology of obesity. This in turn could result in the development of effective treatments of obesity. Further, the work on dietary obesity resistant animals could yield information which would allow for the screening of populations and the detection of individuals at high risk for obesity.
