Role of hypothalamic MC4R in glucose homeostasis via a novel neuroendocrine circuit involving the kidneys and adrenal glands

下丘脑 MC4R 通过涉及肾脏和肾上腺的新型神经内分泌回路在葡萄糖稳态中的作用

• 批准号: 10666539
• 负责人: Kavaljit H Chhabra
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666539
• 关键词: Ablation; Adrenal Glands; Adrenergic Receptor; Affect; Bilateral; Blood Glucose; Cause of Death; Chronic; Corticotropin-Releasing Hormone; Data; Defect; Diabetes Mellitus; Enzymes; Epinephrine; Epithelial Cells; Event; Excision; Exhibits; Failure; GLUT-2 protein; Genes; Gluconeogenesis; Glucose; Glycosuria; Goals; Hypoglycemia; Hypothalamic structure; Impairment; Kidney; Knock-out; Knockout Mice; Life; Link; Longitudinal Studies; Mediating; Melanocortin 4 Receptor; Messenger RNA; Molecular; Mus; Nerve; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peripheral; Pilot Projects; Plasma; Plasma Enhancement; Population; Pro-Opiomelanocortin; Probability; Proximal Kidney Tubules; Publishing; Reagent; Regulation; Reporting; Research Project Grants; Role; SLC2A1 gene; Signal Transduction; Source; System; Testing; Work; absorption; afferent nerve; beta-adrenergic receptor; blood glucose regulation; clinically significant; defined contribution; innovation; knock-down; mad itch virus; mouse model; neural; novel; response; restoration; small hairpin RNA

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 MC4R- expressing 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 life- threatening condition in patients with type 1 or late-stage type 2 diabetes.

我们最近发现下丘脑 MC4R 通过肾上腺素和肾 GLUT2 影响糖尿来调节血糖水平。此外，我们之前已经证明，糖尿病会降低下丘脑 Mc4r 的表达，从而导致小鼠对葡萄糖缺乏的逆调节反应 (CRR) 缺陷。这些具有临床意义的观察结果背后的分子和综合机制仍然未知，具体而言，下丘脑 MC4R 如何调节血浆肾上腺素水平？下丘脑 MC4R 和肾脏 GLUT2 之间的神经串扰通过肾上腺素协调全身葡萄糖稳态的调节？在我们的初步研究中，我们观察到促肾上腺皮质激素释放激素 (CRH) 神经元中的 MC4R 选择性恢复使其他 MC4R 缺陷小鼠的血浆肾上腺素水平正常化，表明表达 MC4R 的 CRH 神经元在调节血浆肾上腺素水平方面具有意想不到的肾脏特异性作用。 Glut2 基因敲除小鼠免受糖尿病介导的 CRR 缺陷导致的低血糖，并且小鼠下丘脑中的 Mc4r 和 Crh mRNA 水平增加，表明肾脏 GLUT2 对下丘脑黑皮质素系统的影响，我们的初步数据也表明了肾脏的贡献，但是。基于这些初步研究，肾脏特异性 Glut2 敲除小鼠发生低血糖后，糖异生作用可恢复正常血糖水平，而不是肝脏。研究结果表明，表达下丘脑 MC4R 的 CRH 神经元在葡萄糖缺乏时被传入肾神经激活，从而增强血浆肾上腺素，从而增加肾糖异生并恢复血糖水平。此外，糖尿病患者肾脏 GLUT2 水平升高会损害这一点。激活表达 MC4R 的 CRH 神经元以损害对低血糖的反调节反应 我们将通过以下目标来测试假设，目标 1：确定。表达下丘脑 MC4R 的 CRH 神经元在整合来自肾传入神经的信号以增加血浆肾上腺素以应对低血糖中的作用目标 2：确定分子和综合（中枢与外周）机制 - 肾 GLUT2 长期升高，肾传入神经活动减少，和/或下丘脑表达 MC4R 的 CRH 神经元的激活减弱 - 糖尿病会通过这种方式损害身体的防御能力目标3：确定肾糖异生作为葡萄糖来源的作用，以预防低血糖，并确定肾肾上腺素受体，肾上腺素通过该受体增加葡萄糖重吸收和肾糖异生。总之，该项目可能会确定一种新的神经内分泌回路。下丘脑、肾脏和肾上腺协调全身葡萄糖稳态，这种整合回路可能会为糖尿病的分子基础提供信息。在面临葡萄糖缺乏时，会损害身体增加血浆肾上腺素的能力，导致低血糖相关的自主神经衰竭，这是 1 型或晚期 2 型糖尿病患者的一种危及生命的疾病。