Short-term overeating induces a hypermetabolic state while the development of chronic obesity, especially in older diabetic rats and humans, is often associated with defective thermogenic capacity and insulin resistance. A multidisciplinary investigation of the mechanism by which this switch in metabolic priorities occurs will characterize the interrelationship of insulin resistance, age, genotype and thermogenic capacity during the development and maintenance of obesity in rats by assessing: 1) sympatho-adrenal system (SAS) function as a primary effector of thermogenesis using plasma catecholamines and organ turnover of norepinephrine; 2) peripheral and central nervous system (CNS) insulin sensitivity using estimates of glucose turnover and the effect of insulin and glucose on the CNS activation of the SAS; 3) function of brown adipose tissue as a major sympathetically controlled thermogenic organ in the rat, using receptor binding, morphological, compositional and functional (lipolysis and oxygen consumption) assays. Initial studies will correlate morphological and functional characteristics of the 2 types of brown adipocytes and this information will be used along with the functional tests listed above to identify the factors which allow adolescent animals and some strains of adult rats (Fischer F-344) to resist the development of diet-induced obesity (DIO) versus the predisposition of other adult rats (Sprague-Dawley) to develop DIO. These results will be compared to those in the genetically obese Zucker rat with specific emphasis on the additional influence of adrenal corticoids on their metabolic abnormalities, as well as the effects of corticoids on the development of DIO in neonatal Sprague-Dawley rats. Since catecholamine-containing pathways in the CNS modulate food intake, SAS activity and thermogenesis, further studies will evaluate the effect of diet, obesity, genotype, age and insulin resistance on the metabolism of CNS catecholamines. The overall goal will be to identify the controlling factors in the development and maintenance of obesity to provide new avenues for therapeutic intervention.
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