Regulation of Adipose Tissue Metabolism by Central Insulin and Leptin

项目总结 白色脂肪组织(WAT)是维持全身糖、脂平衡的重要器官。在……里面 肥胖和2型糖尿病(DM2)，WAT功能受损，导致脂肪沉积在 异位组织，如肝脏和肌肉，糖脂平衡受损，以及慢性 轻度炎症状态。新生脂肪生成作用(DNL)最近已成为一个关键因素 Wat的功能。在该奖项的第一个资助周期内进行的研究做出了贡献 通过证明(1)Wat中的DNL在肥胖症、糖尿病和恶病质中的比例较低 似乎是啮齿动物和人类代谢健康的标志；(2)瘦素和胰岛素 通过大脑瘦素和胰岛素信号控制Wat DNL；以及(3)环境触发 诱发暴饮暴食等代谢综合征损害大脑功能 调节WAT功能的胰岛素信号。 我们的初步数据表明，从AgRP神经元起源的神经元回路在 中脑-基底下丘脑调节Wat DNL和炎症及系统底物 利用率。有趣的是，在高脂喂养(HFD)作为人类肥胖和 代谢综合征，AgRP激活仍然推动食物摄入，但未能控制Wat DNL和 炎症，或底物利用。在恶病质模型中，AgRP的激活不能调节 WAT DNL与炎症、底物利用和食物摄入量。在Aim中，目前的一种 我们的目标是定位起源于AgRP神经元的交感流出通路 突触连接到Wat并从功能上表征AgRP的特定投射 这些神经元中具有不同代谢和消耗功能的AgRP神经元。在目标二中 我们计划研究大脑中胰岛素、葡萄糖和瘦素在调节神经传出中的作用。 起源于AgRP神经元的通路。在目标三中，我们计划测试是否有同情心 神经系统是中枢神经系统调节Wat DNL使用的关键继发机制 研究儿茶酚胺能信号的具体作用的创新方法， 副交感和交感神经支配。了解脂肪组织的功能 可以在肥胖症和糖尿病患者中恢复，这可能表明治疗策略 改善或预防代谢紊乱。

PROJECT SUMMARY White adipose tissue (WAT) is a critical organ in whole body glucose and lipid homeostasis. In obesity and type 2 diabetes (DM2), WAT function is compromised, resulting in lipid deposition in ectopic tissues such as liver and muscle, impaired glucose and lipid homeostasis, and a chronic low grade inflammatory state. De novo lipogenesis (DNL) has recently emerged as a key aspect of WAT function. Studies performed during the first funding cycle of this award have contributed to that notion by demonstrating that (1) DNL in WAT is low in obesity, diabetes and cachexia and seems to be a marker of metabolic health in both rodents and humans; (2) leptin and insulin control WAT DNL via brain leptin and insulin signaling; and (3) environmental triggers that induce the metabolic syndrome such as overeating and binge drinking impair the ability of brain insulin signaling to regulate WAT functionality. Our preliminary data suggest that a neuronal circuit originating from AgRP neurons in the medio-basal hypothalamus regulates WAT DNL and inflammation and systemic substrate utilization. Interestingly, after high fat feeding (HFD) as a model for human obesity and metabolic syndrome, AgRP activation still drives food intake, but fails to govern WAT DNL and inflammation, or substrate utilization. In a model of cachexia, AgRP activation fails to regulate WAT DNL and inflammation, substrate utilization and food intake. In aim one of the current proposal we aim to map the sympathetic outflow pathways originating from AgRP neurons that connect synaptically to WAT and to functionally characterize specific projections of AgRP neurons in these different metabolic and consummatory functions of AgRP neurons. In aim two we plan to examine the role of brain insulin, glucose and leptin in regulating the efferent pathways originating from AgRP neurons. In aim three we plan to test if the sympathetic nervous system is the key relay mechanism through which the CNS regulates WAT DNL using innovative approaches to study the specific roles of catecholaminergic signaling, parasympathetic and sympathetic innervation. Understanding how adipose tissue functionality can be restored in obesity and diabetes may point towards therapeutic strategies that ameliorate or prevent metabolic disorders.