Role of Hypothalamic MC4R in Glucose Homeostasis via a Novel Neuroendocrine Circuit involving the Kidneys and Adrenal Glands

We recently identified the contribution of hypothalamic MC4R in regulating blood glucose levels by influencing glycosuria through epinephrine and renal GLUT2. Moreover, we have demonstrated previously that diabetes decreases the hypothalamic Mc4r expression that consequently leads to defective counterregulatory response (CRR) to glucose deficits in mice. The molecular and integrative mechanisms underlying these clinically significant observations remain unknown. Specifically, how does hypothalamic MC4R regulates plasma epinephrine levels? Does a neural crosstalk between the hypothalamic MC4R and kidney GLUT2 coordinate the regulation of systemic glucose homeostasis via epinephrine? In our Preliminary Studies, we observed that MC4R restoration selectively in the corticotropin releasing hormone (CRH) neurons normalized plasma epinephrine levels in otherwise MC4R- deficient mice, indicating the role of MC4Rexpressing CRH neurons in regulating plasma epinephrine levels. Unexpectedly, kidney-specific Glut2 knockout mice are protected from diabetes-mediated defective CRR to hypoglycemia and the mice show increased Mc4r and Crh mRNA levels in the hypothalamus, suggesting the influence of renal GLUT2 on the hypothalamic melanocortin system. Our Preliminary Data also indicate the contribution of renal, but not liver, gluconeogenesis toward restoration of normal blood glucose levels following hypoglycemia in the kidney-specific Glut2 knockout mice. Based on these preliminary findings, we hypothesize that hypothalamic MC4R-expressing CRH neurons are activated by the afferent renal nerves in response to glucose deficits to enhance plasma epinephrine, which in turn increases renal gluconeogenesis and restores blood glucose levels. Moreover, elevated kidney GLUT2 levels in diabetes compromises this activation of MC4R-expressing CRH neurons to impair counterregulatory response to hypoglycemia. We will test the hypotheses with the following Aims, Aim1: Determine the role of hypothalamic MC4R-expressing CRH neurons in integrating signals from renal afferent nerves to increase plasma epinephrine in response to hypoglycemia. Aim2: Identify the molecular and integrative (central versus peripheral) mechanisms – chronically elevated renal GLUT2, decreased renal afferent nerve activity, and/or blunted activation of hypothalamic MC4R-expressing CRH neurons - through which diabetes compromises the body’s ability to defend against hypoglycemia. Aim3: Establish the contribution of renal gluconeogenesis as a source of glucose to defend against hypoglycemia and identify the renal adrenergic receptors through which epinephrine increases glucose reabsorption and renal gluconeogenesis. Altogether, this project will likely identify a novel neuroendocrine circuit underlying the crosstalk between the hypothalamus, kidney and adrenal gland to coordinate systemic glucose homeostasis. This integrative circuit will probably inform the molecular basis of how diabetes compromises the body’s ability to increase plasma epinephrine in the face of glucose deficits leading to hypoglycemia-associated autonomic failure, a lifethreatening condition in patients with type 1 or late- stage type 2 diabetes.