This project is aimed at elucidating CNS mechanisms that underlie the increase in body adipose mass that is associated with consuming a diet high in dietary fat. CNS systems involved in food intake can be conceptually divided into two categories, anabolic and catabolic. Anabolic effectors are those than when activated, elicit increased food intake, decreased energy expenditure, and consequently increased stored energy in the form of adipose tissue mass. Catabolic effector pathways do just the opposite: decrease food intake, increase energy expenditure and result in decreased adipose tissue mass. A critical part of this feedback model is that hormones responsive to the level of adiposity inhibit anabolic pathways while activating catabolic pathways, and that the balance between these pathways that ultimately the animal's ingestive behavior and defended level of adiposity. The guiding hypothesis underlying this proposal is that high-fat diets increase activity in anabolic effector pathways and/or decrease activity in catabolic effector pathways and thereby produce and maintain a long-lasting and non-compensated mismatch between caloric intake and caloric expenditure. The dietary model and 5 basic groups for individual experiments we propose to use a variety of single and double-labeling techniques in addition to CNS application of peptides to accomplish 3 specific aims: 1) To evaluate the hypothesis that the high-fat diet alters the activity and/or signaling of arcuate nucleus neurons sensitive to the adiposity signals, insulin and leptin. 2) To evaluate the hypothesis that maintenance on a high-fat diet decreases catabolic activity and/or signaling in the paraventricular nucleus. 3) To evaluate the hypothesis that maintenance on a high-fat diet alters sensitivity to a variety of hypothalamic peptides when administered into the CNS. Understanding how brain mechanisms associated with the normal regulation of food intake and body weight are altered by high-fat diets is a critical component to understanding how high-fat diets promote obesity. Information from the execution of these experiments will provide insight into these mechanisms and point to potential novel therapeutic strategies particularly when combined with information from the other 2 projects.
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