Function of the hypothalamic melanocortin system in stimulating counter-regulatory response to hypoglycemia

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The primary goal of this K01 award application is to acquire necessary training and research experience to facilitate my transition to an independent research career. So far in my postdoctoral training, I have applied my skills and knowledge that were learned during my PhD education in Dr. Eric Lazartigues' lab. Moving forward, I would like to acquire new research skills and develop a project that is different from Dr. Malcolm Low's (my postdoc mentor) ongoing research. I would like to integrate my current skills in studying peripheral organs with new techniques pertaining to the central nervous system. I will undertake training and courses in neuropharmacology, neuroanatomy, developing transgenic mouse models employing opto- and pharmaco- genetic tools. My long term career goal is to become an independent investigator at a major academic research-focused institution and to contribute toward our understanding of the function of brain in glucose homeostasis. Patients with both type 1 and type 2 (late stage) diabetes are at high risk of facing life-threating hypoglycemia due to tight glucose control therapy. Normally, hormones such as epinephrine and glucagon are released to counteract hypoglycemia; however, patients with diabetes exhibit impaired counter-regulatory response to hypoglycemia. Consequently, the function of brain deteriorates due to lack of glucose and these patients may experience confusion, seizures, unconsciousness, and death if not treated immediately. During K01 award period, I aim to determine the central pathways involved in hypoglycemia counter-regulation. My preliminary data suggest that hypothalamic melanocortin system is essential in counteracting hypoglycemia. Arcuate nucleus-specific Pomc knockout mice (ArcPomc-/-) exhibit impaired response to glucose deficit. Therefore, in Aim 1, I will determine a physiological role of hypothalamic POMC in counteracting hypoglycemia. I will employ immunohistochemistry, in situ hybridization, and hypoglycemic clamps to accomplish Aim 1. I have observed that melanocortin 4 receptor (MC4R) agonist treatment improves, while its antagonist worsens, the counter-regulatory response in ArcPomc-/- and WT mice, respectively. Hence, Aim 2 of this project is to examine the function of the MC4R specifically in the paraventricular nucleus of the hypothalamus (PVH, a region that regulates sympathetic nervous system activity) in stimulating counter-regulatory response to hypoglycemia. I will employ opto- and pharmaco- genetic tools to elucidate the role of MC4RPVH in hypoglycemia counter-regulation. Finally, in Aim 3, I will examine the impact of diabetes on hypothalamic POMC and MC4R levels to ascertain the mechanism underlying reduced response to hypoglycemia during diabetes. Moreover, I will test the potential of MC4R agonist in preventing life- threatening hypoglycemia in streptozotocin (STZ) treated mice with diabetes. The outcome of this project will have direct implication for prevention of fatal hypoglycemic episodes in patients with diabetes. Importantly, with the progress of this project, I will be able to acquire expertise in the aforementioned techniques, and generate data for future studies and applications for R03 and R01 grants. My mentoring committee includes a number of scientists, with outstanding careers, that will provide guidance of the highest possible level for all of the aims of this project. The University of Michigan along with its Diabetes Research Center will provide me an excellent facility to successfully complete my project.