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

POMC神经元（Parton，Nature 2007）和MCH神经元（Kong，Cell Metabolism，2010）的葡萄糖感知 在控制外周葡萄糖稳态中起重要作用。传感由“β细胞”介导。 类似机制（葡萄糖- ATP -KATP通道关闭-去极化）， 高脂肪饮食引起的肥胖。UCP 2可能是肥胖诱导的葡萄糖感知丧失的介质。我们 假设这些神经元的葡萄糖感知缺陷对糖尿病的发病机制有重要作用， 2型糖尿病这在Aim 1中通过选择性地删除POMC和MCH神经元中的UCP 2进行了测试。 目的2-4：POMC神经元的异源性。POMC神经元调节体重和葡萄糖 体内平衡一般来说，该领域已经将弓状核中的POMC神经元视为一个同质组-所有 响应相同的输入，并且都执行相同的功能。或者，很可能， POMC神经元的功能不同子集，它们对不同的输入做出反应并投射到不同的信号 大脑的不同区域，从而调节不同的功能。相关的是，只有POMC神经元的一个子集能够感知 葡萄糖，这种能力是由表达含Suri的KATP通道赋予的;非葡萄糖 传感亚群不表达Sur 1。另一方面，瘦素反应性POMC神经元表达瘦素， 受体（LEPRs），但不是Suri。因此，该建议假设存在POMC的两个子集 神经元-葡萄糖感应神经元，以Suri为标志，调节葡萄糖稳态，和瘦素反应 神经元，以LEPRs为标志，调节能量平衡。在这项研究中，基因 方法和DREADD技术将用于建立解剖结构（投影部位）和功能 （葡萄糖与体重调节）这两个群体的POMC神经元。这些研究应 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。

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.