The physiological importance of central nervous system (CNS) regulation of metabolic fuels is well recognized, yet there is a resounding lack of systematic, coherent knowledge of the CNS control of metabolic fuels. This is both surprising and unfortunate: the CNS is the main regulator of energy stores and their replenishment, and the driving force behind changes in metabolic fuels during physiological or psychological stress. Disturbances of metabolic fuel regulation have definite pathologic consequences (e.g., retinopathy, nephropathy, hyperlipemia, atherosclerosis). The experiments proposed will use direct microinfusions of specific agonists and antagonists into the rat brain, and transections of brain pathways, to continue the systematic development of knowledge of the CNS control of blood glucose and free fatty acids, the two major metabolic fuels. These studies will determine the exact brain sites where beta-adrenergic, alpha-adrenergic, and histaminergic agonists affect metabolic fuel regulation, and which receptor types mediate these effects. Additional studies measuring blood insulin, glucagon, and catecholamines will determine the peripheral mechanisms which produce the changes seen in blood glucose and free fatty acids. Routine measurement of blood corticosterone, plus additional studies on gastric secretion, will show how specific these effects are for metabolic fuel regulation. Brain pathway transection studies will indicate the crucial pathways connecting regions mediating these effects. Agent interaction studies at specific sites will outline the pharmacological organization of processing at these sites. These studies will develop significant knowledge on the roles of central beta-adrenergic, alpha-adrenergic, and histaminergic systems in the CNS control of the metabolic fuels, glucose and free fatty acids. These studies will be crucial in designing future work measuring changes in specific neurotransmitter activities at specific sites during normal physiological events. The knowledge obtained will also be relevant to other fields, including the regulation of food intake and body weight and associated pathologies, CNS control of corticosterone secretion, control of adrenal catecholamine secretion, and neural control of the endocrine pancreas.
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