NEUROBEHAVIORAL ANALYSIS OF GLUCAGON SATIETY

DESCRIPTION: This revised application proposes continued neurobehavioral analysis of glucagon's role in the control of postprandial satiety. The effects of glucagon on spontaneous meals in free-feeding rats as well as on scheduled test meals of a palatable food will be investigated to characterize further the contexts in which glucagon controls feeding, to elucidate endocrine, metabolic, and neural mechanisms underlying glucagon's satiating action, and to establish its role in the regulation of body weight. The sensitivity and physiological relevance of the proposed experiments are increased by testing spontaneous meals using a remotely-located, computerized systems to control meal-contingent glucagon infusions that mimic the physiological pattern of endogenous glucagon release and to collect data. The scientific importance of this problem is indicated by demonstrations that endogenous glucagon is necessary for the normal control meal size in rats and that infusion of apparently physiological glucagon doses reduce meal size in humans in the absence of physical or subjective side effects. Progress in the analysis of glucagon's satiating action will advance understanding of the physiological controls of food intake, a problem whose solution is prerequisite for the development of physiologically-based treatments of human eating disorders. Furthermore, recent research has revealed changes in glucagon physiology in human disorders, including obesity and NIDDM, that suggest that pathophysiology of glucagon's satiating action may play an etiological role in some disordered human eating. The revised proposal has seven Specific Aims: Specific Aim 1 is to determine the effects of antagonism of the hepatocyte glucagon receptor on the satiating effects of exogenous and endogenous glucagon. Aim 2 is to compare hepatic portal vein and hepatic vein plasma glucagon levels during nocturnal spontaneous meals in undisturbed rats with those elicited by satiating doses of glucagon. Aim 3 is to determine whether glucagon receptors occur on abdominal vagal afferents. Aim 4 is to determine whether gastric or intestinal food stimuli are sufficient to reinstate the satiating effect of exogenous glucagon in rats sham feeding with open gastric cannulas. Aim 5 is to determine the effects of exogenous and endogenous glucagon on the microstructure of ingestive behavior and on behaviors associated with meals. Aim 6 is to determine whether pancreatic amylin mediates glucagon's satiating action. Aim 7 is to identify brain areas mediating peripheral glucagon's satiating action by using c-fos immunocytochemistry.