Regulation of adipose tissue metabolism by central insulin and leptin

描述（由申请方提供）：内脏肥胖是发生2型胰岛素抵抗的主要风险因素。糖尿病及其并发症血脂异常和心血管疾病。脂肪组织是一种重要的内分泌器官，通过瘦素、脂联素等脂肪因子、脂肪酸释放和神经传入调节能量平衡、糖脂代谢。胰岛素和瘦素是两种主要的肥胖激素，其已被证明通过中枢即脑信号传导在很大程度上调节食物摄入和葡萄糖通量。瘦素减少肥胖，胰岛素主要通过抑制脂解增加脂肪组织中的脂质储存。胰岛素对脂解的抑制作用被认为是由脂肪细胞中的胰岛素信号传导介导的。大脑通过自主神经系统控制脂肪组织代谢的机制还知之甚少。我们实验室以前的工作已经证明，瘦素通过下丘脑中-基底节（MBH）抑制脂肪组织中的脂肪生成并诱导脂肪分解，并且需要脂肪组织的完整交感神经支配。由于胰岛素对脂肪代谢的生理作用与胰岛素相反，我们推测胰岛素的部分促脂肪生成和抗脂肪分解作用是由脑胰岛素信号传导介导的。事实上，我们已经做出了新的观察，即输注到第三脑室或MBH中的胰岛素有效地抑制全身和脂肪组织脂解，并诱导脂肪组织脂肪生成蛋白表达，而不依赖于循环胰岛素和葡萄糖水平或食物摄入的变化。因此，我们建议的中心假设是，瘦素和胰岛素对内脏脂肪组织代谢产生相反的影响。我们希望表征在生理和病理生理学（饮食、炎症和遗传性胰岛素抵抗）背景下参与脂肪组织代谢和脂质通量的脑控制的中枢和外周通路，以了解脂肪组织代谢的脑控制受损是否有助于胰岛素抵抗状态下的不受限制的脂解。这些研究应该促进我们对大脑如何通过调节营养分配来控制WAT代谢和肥胖的理解，而不依赖于食物摄入。 公共卫生相关性：内脏肥胖是胰岛素抵抗、2型糖尿病及其合并症血脂异常和心血管疾病的主要危险因素。在这里，我们提供的证据表明，两个主要的肥胖激素瘦素和胰岛素调节内脏肥胖和脂肪分解通过大脑。拟议研究的目标是从机制上探索所涉及的中枢信号通路和发挥这种脂肪组织代谢的大脑控制的中继机制，以及脂肪分解的大脑控制受损是否有助于胰岛素抵抗和2型糖尿病。

DESCRIPTION (provided by applicant): Visceral adiposity is a major risk factor for the development of insulin resistance, type 2. diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Adipose tissue has been recognized to be an important endocrine organ that regulates energy homeostasis, glucose and lipid metabolism via adipokines like leptin and adiponectin, fatty acid release and possibly neuronal afferens. Insulin and leptin are two of the major adiposity hormones that have been shown to regulate food intake and glucose fluxes to a large extend via central, i.e. brain signaling. While leptin decreases adiposity, insulin increases lipid storage in adipose tissue chiefly by suppressing lipolysis. The inhibition of lipolysis by insulin is believed to be mediated exclusively by insulin signaling in adipocytes. The brain control of adipose tissue metabolism via the autonomic nervous system is poorly understood. Previous work from our lab has demonstrated that leptin suppresses lipogenesis and induces lipolysis in adipose tissue via the medio-basal hypothalamus (MBH) and requires intact sympathetic innervation of adipose tissue. Since insulin exerts the opposite physiological effects on adipose metabolism then insulin, we speculated that part of insulins prolipogenic and antilipolytic effects are mediated by brain insulin signaling. Indeed, we have made the novel observation that insulin infused into the third ventricle or the MBH potently suppresses whole body and adipose tissue lipolysis and induces adipose tissue lipogenic protein expression independent of changes in circulating insulin and glucose levels or food intake. Thus, the central hypothesis of our proposal is that leptin and insulin exert opposing effects on visceral adipose tissue metabolism. We wish to characterize the central and peripheral pathways that participate in the brain control of adipose tissue metabolism and lipid fluxes in physiological and pathophysiological (dietary, inflammatory and genetic insulin resistance) contexts to understand if impaired brain control of adipose tissue metabolism contributes to the unrestrained lipolysis in the insulin resistant state. These studies should advance our understanding of how the brain controls WAT metabolism and adiposity independent of food intake by regulating nutrient partitioning. PUBLIC HEALTH RELEVANCE: Visceral adiposity is a major risk factor for the development of insulin resistance, type 2 diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Here we provide evidence that the two major adiposity hormones leptin and insulin regulate visceral adiposity and lipolysis via the brain. The goal of the proposed studies is to mechanistically explore the central signaling pathways involved and the relay mechanism that exert this brain control of adipose tissue metabolism and whether impaired brain control of lipolysis contributes to insulin resistance and type 2 diabetes.