Regulation of adipose tissue metabolism by central insulin and leptin

描述(申请人提供)：内脏肥胖是发展胰岛素抵抗、2型糖尿病及其血脂异常和心血管疾病共病的主要危险因素。脂肪组织被认为是一个重要的内分泌器官，通过瘦素和脂联素等脂肪因子、脂肪酸释放以及可能的神经元传入来调节能量稳态、糖脂代谢。胰岛素和瘦素是两种主要的肥胖激素，已被证明在很大程度上通过中枢，即大脑信号来调节食物的摄入和葡萄糖的流动。虽然瘦素可以降低肥胖，但胰岛素主要通过抑制脂肪分解来增加脂肪组织中的脂肪储存。胰岛素抑制脂肪分解的作用被认为完全是通过脂肪细胞中的胰岛素信号来实现的。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。本实验室以前的工作表明，瘦素通过下丘脑中基底核(MBH)抑制脂肪组织中的脂肪生成和诱导脂肪分解，并需要脂肪组织完整的交感神经支配。由于胰岛素对脂肪代谢的生理作用与胰岛素相反，我们推测部分胰岛素的促脂肪和降脂作用是由脑胰岛素信号介导的。事实上，我们已经做出了新的观察，胰岛素注入第三脑室或MBH可以有效地抑制全身和脂肪组织的脂肪分解，并诱导脂肪组织脂肪组织脂肪蛋白的表达，而不依赖于循环中胰岛素和葡萄糖水平或食物摄入量的变化。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的代谢起相反的作用。我们希望在生理和病理生理(饮食、炎症和遗传胰岛素抵抗)的背景下，确定参与大脑控制脂肪组织代谢和脂通量的中枢和外周通路的特征，以了解大脑对脂肪组织代谢的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。这些研究应该会促进我们对大脑如何通过调节营养分配来控制水分代谢和肥胖的理解，而不是依赖于食物的摄入量。公共卫生相关性：内脏肥胖是胰岛素抵抗、2型糖尿病及其血脂异常和心血管疾病共病的主要危险因素。在这里，我们提供了两种主要的肥胖激素瘦素和胰岛素通过大脑调节内脏脂肪和脂肪分解的证据。这项研究的目的是从机制上探索大脑控制脂肪组织代谢的中枢信号通路和继发机制，以及大脑对脂肪分解的控制受损是否会导致胰岛素抵抗和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.