The regulatory mechanisms underlying feeding behavior and the development and sustaining of obesity will be studied in two models of obesity in rhesus monkeys and their non-obese controls. Using a method of forced overfeeding of young adult monkeys to produce experimentally-induced obesity, we have found that monkeys vary in their propensity to sustain that obesity. We will seek to understand what factors present in, or inducible in young adult monkeys predispose to, or are associated with, this sustaining of obesity following forced overfeeding. Our second model of obesity involves the study of a large group of middle-aged and aging rhesus monkeys which have now been characterized and shown to fall into four subsets: i) aging normal weight, ii) aging obese with normoinsulinemia, iii) aging obese with hyperinsulinemia, and iv) aging obese diabetics (non-insulin-dependent diabetes mellitus). We hypothesize that the same factors which differentiate those young adult monkeys that stay obese following overfeeding from those that return to normal body weight, will be associated with the propensity (or lack thereof) to develop spontaneous middle-age-onset obesity. Studies will include measures of feeding behavior, feeding, efficiency, physical activity, adipose tissue morphology and metabolism, adipose tissue lipoprotein lipase, basal and stimulated plasma levels of key hormones, and in vivo methods of assessment of insulin sensitivity, including euglycemic clamps. The extent to which aging affects the likelihood of sustaining obesity induced by transient overfeeding will be determined. Two methods of weight reduction of total caloric intake-by restriction of meal size while retaining normal meal pattern, and by quinine adulteration of the diet, will be used to test the degree to which both forms of obesity (induced vs. spontaneous) are defended. We will also test whether the differences observed between monkeys in the effects of variations in nutrient composition on appetite are associated with the differential propensity to develop and sustain obesity. Collaborative efforts will permit the determination of body composition during all stages of the induction and remission of both experimentally induced and spontaneous obesity, and will permit the further refinement and validation of in vivo methods with in vitro biochemical determinations of body composition. These primte models of human obesity, therefore, provide unique opportunities to combine physiological, biochemical, and behavioral methods under well controlled laboratory conditions in longitudinal studies of the regulation of food intake and adiposity, and are ultimately aimed at potential improvement in the methods of managing obesity.
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