This proposal is concerned with an analysis of two effects of food stimuli-- postprandial satiety and reward. The analysis consists of determining the adequate food stimuli and their specific preabsorptive and/or postabsorptive sites of action. Then these peripheral stimuli are used to identify the peripheral mechanisms activated by food stimuli and the central mechanisms that are altered by food stimuli. The analysis of postprandial satiety has led to the realization that a number of satiety signals arise from food stimuli acting preabsorptively on the surface of the gut from the mouth to the end of the small intestine. This has suggested that preabsorptive satiety mechanisms may be altered in human and animal syndromes of hyperphagia and obesity. We investigate this possibility in the genetically obese (obob) mouse, in the ventromedial hypothalamic lesioned rat and in the normal rat during noctural hyperphagia. Cholecystokinin (CCK) is a putative satiety signal from the small intestine and thus a potential therapeutic agent for obesity. I propose to study its effectiveness during chronic treatment of obob mice. Abdominal vagotomy has also been proposed as a treatment for severe obesity. I propose to investigate its effect on preabsorptive satiety, its effect on food intake and body weight in obob mice, and the mechanism(s) by which it produces numerous deficits in thirst. The analysis of food reward will provide fundamental knowledge about its physiological mechanisms and it is likely to provide new experimental approaches to, and potential therapies for, human feeding disorders.
