MECHANISM OF NEURONAL REGULATION BY LEPTIN AND INSULIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 黑素皮质素神经元受瘦素和葡萄糖以及其他营养状态信号的调节。这些信号到达神经元是因为正中隆起处有一道漏水的血脑屏障。在肥胖症中，瘦素似乎不再调节黑素皮质素系统。我们正在测试这样一种假设，即瘦素被排除在大脑之外是因为血脑屏障发生了变化，并且在肥胖小鼠的中间隆起处变得更不容易渗透。我们还在进行测试，以确定肥胖是否导致黑素皮质素神经元葡萄糖感知的丧失，以及这种葡萄糖感知的丧失是否会导致全身葡萄糖稳态的变化。具体地说，我们一直在测试肥胖导致的黑素皮质素对葡萄糖的抵抗是否会释放肝脏的紧张性抑制，并允许肝脏分泌更多的葡萄糖，从而需要更多的胰岛素来将血糖水平控制在正常范围内。我们正在肥胖的葡萄糖耐受小鼠身上测试这一假说。这两个假说都有可能产生治疗肥胖症和早期II型糖尿病的新治疗策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Melanocortin neurons are regulated by leptin and glucose, and other signals of nutritional state. These signals reach the neurons because of a leaky blood brain barrier at the median eminence. In obesity, it appears that leptin no longer regulates the melanocortin system. We are testing the hypothesis that leptin is excluded from the brain because the blood brain barrier changes, and becomes less permeable at the median eminence of obese mice. We are also testing to determine if obesity causes a loss of glucose sensing in melanocortin neurons, and if this loss of glucose sensing causes changes in systemic glucose homeostasis. Specifically we have been testing if obesity-induced melanocortin resistance to glucose releases the liver from a tonic inhibition, and allows the liver to secrete more glucose, requiring more insulin to control blood glucose levels in a normal range. We are testing this hypothesis in obese glucose intolerant mice. Both of these hypotheses have the potential to generate new therapeutic strategies to treat obesity and early Type II diabetes.