THE ARCUATE K ATP CHANNEL IN HEALTH, OBESITY AND DIABETE

本研究探讨了饮食诱导的肥胖症（DIO）和非胰岛素依赖型糖尿病（NIDDM）对弓状核（ARC）神经元ATP敏感性K+（K-ATP）通道的影响，该通道整合能量平衡的代谢信号。 总体目标是研究弓状葡萄糖敏感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腺β细胞的了解，其中ATP是K-ATP通道活性和胰岛素分泌的关键调节剂。 假设II是调节能量稳态的中枢和外周信号也将通过其对磷酸化的作用来调节ARC K-ATP通道。 将使用分离细胞以及完整脑切片中ARC K-ATP通道电流的全细胞和单通道膜片钳记录来检验这些假设。 这些研究将为大脑控制肥胖和糖尿病患者葡萄糖代谢变化的方式提供新的见解。

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.