MECHANISM OF NEURONAL REGULATION BY LEPTIN AND INSULIN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 黑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的血脑屏障渗漏。在肥胖症中，瘦素似乎不再调节黑皮质素系统。我们正在测试这样的假设：由于血脑屏障发生变化，瘦素被排除在大脑之外，并且在肥胖小鼠的中位隆起处变得不那么具有渗透性。我们也在测试肥胖是否会导致黑皮质素神经元的葡萄糖感知功能丧失，以及这种葡萄糖感知功能的丧失是否会导致全身葡萄糖稳态的变化。具体来说，我们一直在测试肥胖诱导的黑皮质素对葡萄糖的抵抗是否会使肝脏从紧张性抑制中释放出来，并允许肝脏分泌更多的葡萄糖，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不耐受小鼠中检验这一假设。 这两种假设都有可能产生新的治疗策略来治疗肥胖和早期II型糖尿病。

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.