Oxytocin responses to insulin and glucose: Impact of lactation and obesity

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DESCRIPTION (provided by applicant): Glucokinase and insulin receptors (InsR) are abundant in the hypothalamic supraoptic nucleus (SON). The goal of this application is to develop background information to determine if the oxytocin (OT) neurons in SON utilize these molecules to monitor body nutrient status. The presence of glucokinase in other neurons and cells that function as glucose sensors (e.g. pancreatic beta cells and neurons in recognized appetite regulating centers) suggests that glucose-sensitivity may allow the OT neurons to monitor extracellular glucose and thereby respond appropriately to induce anorexia after a meal. Insulin is also recognized as a satiety-inducing signal. Thus, the presence of InsR in OT neurons may provide a second mechanism for the OT neurons to monitor changes in body nutrient status. Since OT is a recognized anorexic agent (e.g. suppresses food intake), alterations in the control of OT secretion may contribute to obesity and/or provide alternate treatment strategies to prevent or reverse obesity. The specific aims of the proposal are: 1. To test the hypothesis that magnocellular OT neurons function as glucose sensors and monitor hormonal indices of body nutrient stores. 2. To test the hypothesis that lactation alters the effect of glucose and insulin on OT release. 3. To test the hypothesis that the role of glucokinase and InsR in SON is altered by diet- induced obesity. Explants of the hypothalamo-neurohypophyseal system (HNS) will be used to determine the effect of glucose and insulin on OT and VP release and to determine if intracellular calcium ([Ca2+]i) signaling is altered in OT and VP SON neurons by glucose and/or insulin. Both hypothalamic and neural lobe hormone release will be monitored, because OT acts centrally to induce anorexia, and dendritic and/or en passant axonal OT release is thought to be the source of ligand for OT receptors (OTR) in 'satiety neurons' of the ventromedial nucleus. Since lactation is associated with both stimulation of OT release and increased food intake, it is possible that the impact of glucose and insulin on OT release is altered during lactation and that similar changes contribute to the difficulty that obese individuals experience in reducing food intake.