Obesity when viewed in the broadest sense is a disorder of energy balance. There is evidence that in a number of genetic models of obesity, thermogenesis is defective and the major site of this defect is brown adipose tissue. The bulk of this evidence comes from animals where the obesity is already established. What is not known is whether thermogenic alterations occur early enough to significantly contribute to the ontogeny of obesity. In this proposal we will evaluate this problem in the genetically obese Zucker rat. In addition, we will examine 3 genetically lean strains of rats that achieve different degrees of obesity as adults after overfeeding during weaning as well as after weaning. The intent is to determine if thermogenic alterations are associated with the development of different degrees of obesity. We are asking 4 specific questions: 1) How early are alterations in thermogenesis manifested in the genetically obese and genetically lean overfed animals? 2) Does overfeeding during suckling affect postweaning thermogenic responses to palatable diets and do these responses vary depending on the strain of rats? 3) Do the initial thermogenic alterations reflect alterations at the target tissues effecting nonshivering thermogenesis? 4) Do alterations in thermogenic capacity of brown adipose tissue occur concurrently with the rats' altered response to norepinephrine? These questions will be answered using a variety of techniques including measurements of whole animal thermogenesis and composition, morphological examination of brown and white adipose tissue (cell size and number), biochemical analyses including measurements of lipogenesis, cytochrome c and activities of citrate synthase, beta-hydroxyacyl CoA dehydrogenase and lipoprotein lipase. The data will provide basic information about thermogenesis in neonates and how this is altered in obesity. Furthermore, this study will indicate the degree to which thermogenic alterations contribute to the early development of obesity. Of practical significance are preliminary observations by a number of investigators that thermogenesis and brown adipose tissue may be impaired in obese adult humans. Our basic findings should help to evaluate and target treatment aimed at modifying this defect.
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