NEURAL SUBSTRATES OF METABOLIC CONTROLS OF INGESTION

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It is generally assumed that signals of metabolic origin contribute to the control food intake. Evidence that food intake is controlled by variations in the availability or utilization of specific nutrients has been derived from studies using inhibitors of specific metabolic pathways. For example, it is now known that inhibition of glucose metabolism and, under appropriate circumstances, fatty acid metabolism, increase food intake. Nevertheless, despite the availability of pharmacological tools for blocking glucose and fat metabolism, the precise anatomical substrates and the neurobehavioral mechanisms by which reduced substrate metabolism increases food intake are not known. One series of experiments proposed in this application will examine the relative importance of central and peripheral neural substrates for the detection of specific metabolic stimuli for the initiation of feeding. In particular, these experiments will focus on the caudal brainstem and the hepatic branch of the vagus since these structures appear to contain chemoreceptors crucial for stimulation of feeding by decreased glucose and fatty acid oxidation. Anatomical studies using pathway tracing techniques (silver stain and horseradish peroxidase) and behavioral studies of lesioned rats are planned to obtain additional information regarding the neural pathways involved in these controls of feeding. in addition, the existence and localization of receptors for mobilization of substrates in response to reduced fatty acid oxidation will be investigated. A second group of experiments investigates the interaction of glucose and fat metabolism in the control of food intake using behavioral studies of normal rats and lesioned rats in which the neural substrate for one of these controls has been destroyed. Finally, the effect of specific pharmacologically-induced blockade of glucose and fatty acid utilization on self-selection of dietary macronutrients and on gustatory responsiveness to specific macronutrients will be investigated. Both normal animals and animals with lesion-induced deficits in the control of food intake by glucoprivation and reduced fatty acid oxidation will be studied. These studies should provide a better understanding of the mechanisms by which metabolic stimuli participate in the control of both normal and abnormal feeding behavior.