Glucose-Sensing by Neurons: Its Importance and the Role of UCP2

神经元的葡萄糖感应：其重要性和 UCP2 的作用

• 批准号: 8583318
• 负责人: BRADFORD B LOWELL
• 金额: $ 38.39万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583318
• 关键词: Anatomy; Beta Cell; Blood Glucose; Body Weight; Brain; Brain region; Cells; Complex; Diet; Fatty acid glycerol esters; Genetic; Glucose; Heterogeneity; Instruction; Insulin; Leptin; Mediating; Mediator of activation protein; Metabolism; Nature; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Peripheral; Physiological; Play; Population; Role; SF1; Site; Structure of nucleus infundibularis hypothalami; Technology; Testing; Work; blood glucose regulation; diabetes mellitus therapy; energy balance; insight; leptin receptor; neuromechanism; prevent

Glucose-sensing by POMC neurons (Parton, Nature 2007) and MCH neurons (Kong, Cell Metabolism, 2010) plays an important role in controlling peripheral glucose homeostasis. Sensing is mediated by a "beta-cell" like mechanism (glucose - ATP - closure of KATP channels - depolarization), which becomes defective with high fat diet-induced obesity. UCP2 is a likely mediator of obesity-induced loss of glucose sensing. We hypothesize that defective glucose-sensing by these neurons contributes importantly to the pathogenesis of type 2 diabetes. This is being tested in Aim 1 by deleting UCP2 selectively in POMC and MCH neurons. Aims 2-4: Heterogeneity of POMC neurons. POMC neurons regulate both body weight and glucose homeostasis. In general, the field has viewed POMC neurons in the arcuate as a homogenous group - all responding to the same inputs, and all performing the same functions. Alternatively, and likely, there are functionally distinct subsets of POMC neurons, which respond to different inputs and project to different regions of the brain, thus mediating different functions. Of relevance, only a subset of POMC neurons sense glucose, and this capacity is conferred by expression of Suri-containing KATP channels; non-glucose sensing subsets do not express Sur1. Leptin-responding POMC neurons, on the other hand, express leptin receptors (LEPRs), but not Suri. Thus, this proposal hypothesizes that there are two subsets of POMC neurons - glucose-sensing neurons, marked by Suri, which regulate glucose homeostasis, and leptinresponding neurons, marked by LEPRs, which regulate energy balance. In this proposal, genetic approaches and DREADD technology will be used to establish the anatomy (site of projections) and function (glucose- versus body weight-regulating) of these two populations of POMC neurons. These studies should provide new insight into neural mechanisms regulating glucose homeostasis and energy balance.

POMC神经元和MCH神经元的葡萄糖感觉(Parton，自然2007)和MCH神经元(Kong，细胞代谢，2010) 在控制外周血糖动态平衡方面起着重要作用。感觉是由“β细胞”调节的。 类机制(葡萄糖-ATP-KATP通道关闭-去极化)，这变得有缺陷 高脂饮食导致肥胖。UCP2可能是肥胖引起的葡萄糖感觉丧失的介体。我们 假设这些神经元的葡萄糖感知缺陷在糖尿病的发病机制中起重要作用。 2型糖尿病。在AIM 1中，通过选择性地删除POMC和MCH神经元中的UCP2来测试这一点。 目标2-4：POMC神经元的异质性。POMC神经元同时调节体重和血糖 动态平衡。总体而言，该领域将弓状核中的POMC神经元视为一个同质的组-ALL 响应相同的输入，并且都执行相同的功能。或者，也很有可能，还有 在功能上不同的POMC神经元子集，它们对不同的输入做出反应并投射到不同的 大脑的各个区域，因此调节不同的功能。相关的是，只有POMC神经元的子集感觉 葡萄糖，这一能力是由含有苏里的KATP通道的表达所赋予的；非葡萄糖 感测子集不表达Sur1。另一方面，瘦素反应的POMC神经元表达瘦素 受体(LEPR)，但不是Suri。因此，该提议假设POMC有两个子集 神经元-以Suri为标志的葡萄糖敏感神经元，调节葡萄糖稳态和瘦素反应 神经元，以LEPR为标志，调节能量平衡。在这项提案中，基因 将使用入路和DREADD技术来建立解剖结构(投影位置)和功能 (葡萄糖对体重的调节)这两组POMC神经元。这些研究应该 为调节葡萄糖稳态和能量平衡的神经机制提供了新的见解。