A novel brain-to-pancreatic islet neural circuit regulates glucose homeostasis

Project Summary Glucose-sensing neurons in the brain respond to glucose fall by altering their firing activities, which trigger counterregulatory responses to prevent severe hypoglycemia. One essential process of the central nervous system in the maintenance of blood glucose levels is through the regulation of pancreatic islets. The ventromedial hypothalamus (VMH) is a critical component of neural networks that regulate blood glucose. Neurons express vesicular GABA transporter (Vgat) are concentrated in the ventrolateral part of VMH (vlVMH). We found that the majority of these VgatvlVMH neurons are glucose-inhibited (GI) neurons. Activation of these GI-VgatvlVMH neurons will reduce insulin secretion to increase blood glucose under hypoglycemia conditions. Following our pilot observations, we will combine neural circuits mapping, fiber photometry, electrophysiology, optogenetics, and chemogenetics to test the hypothesis that VgatvlVMH neurons regulates glucose homeostasis by changing insulin and glucagon secretion via the brain-to-pancreatic islet pathway. Aim 1 will establish the physiological functions of VgatvlVMH neurons in animals under different conditions (e.g. hyperglycemic, obesity, and diabetes) and further confirm their roles in regulating blood glucose levels. Aim 2 will determine if the VgatvlVMH-originated neural circuits contribute to glucose homeostasis via regulating pancreatic islet function. In aim 3, we will identify the VgatvlVMH neurons that regulate blood glucose via sympathetic pancreatic-projecting tyrosine hydroxylase (TH) neurons. The accomplishment of these studies may reveal the important functions of a novel brain-to-pancreatic islet neural circuit in regulating insulin secretion that has never been studied before. More importantly, we will delineate a new molecular target for glucose homeostasis, which may provide a framework for the development of novel therapeutic strategies for diabetes and obesity.