THE ARCUATE K ATP CHANNEL IN HEALTH, OBESITY AND DIABETE

本研究旨在研究饮食诱导肥胖(DIO)和非胰岛素依赖型糖尿病(NIDDM)对弓状核(ARC)神经元上整合能量平衡代谢信号的ATP敏感性钾通道(K-ATP)的影响。总体目标是研究弓状葡萄糖感受器神经元感知和响应葡萄糖稳态变化的机制。为了实现这一目标，将使用DIO和NIDDM的啮齿动物模型来检验以下两个假设。假设I是K-ATP通道通过响应细胞内ATP的变化来调节ARC神经元上动作电位的产生。这一假说源于我们对胰岛β细胞的了解，在该细胞中，ATP是K-ATP通道活性和胰岛素分泌的关键调节因子。假说II认为，调节能量稳态的中枢和外周信号也将通过它们对磷酸化的影响来调节ARC K-ATP通道。这些假说将使用分离细胞和完整脑片中ARC K-ATP通道电流的全细胞和单通道膜片钳记录来验证。这些研究将为肥胖和糖尿病患者的大脑控制和受糖代谢变化的控制方式提供新的见解。

This proposal examines the effects of diet-induced obesity (DIO) and non-insulin dependent diabetes mellitus (NIDDM) on the ATP-sensitive K+ (K-ATP) channel located on neurons in the arcuate nucleus (ARC) which integrate metabolic signals concerning energy balance. The overall objective is to investigate the mechanisms by which arcuate glucosensing neurons sense and respond to changes in glucose homeostasis. To achieve this objective the following two hypotheses will be tested using a rodent model of DIO and NIDDM. HYPOTHESIS I is that the K-ATP channel regulates the generation of action potentials on ARC neurons by responding to changes in intracellular ATP. This hypothesis derives from our knowledge of the pancreatic beta-cell in which ATP is a critical regulator of K-ATP channel activity and insulin secretion. HYPOTHESIS II is that central and peripheral signals which regulate energy homeostasis will also regulate the ARC K-ATP channel via their effects on phosphorylation. These hypotheses will be tested using whole cell and single channel patch clamp recordings of ARC K-ATP channel currents in isolated cells as well as intact brain slices. These studies will provide new insights into the way in which the brain controls and is controlled by changes in glucose metabolism in obesity and diabetes.