Central Regulation of Hepatic Energy Stores

描述（由申请人提供）：瘦素是一种脂肪细胞衍生的激素，其以与身体脂肪质量成比例的水平循环，其将丰富的外周能量储存传递到大脑。我们先前已经表明，瘦素通过激活交感神经系统集中作用于抑制肝脏脂质含量;我们进一步表明，PI 3 K信号通路中的中枢瘦素抵抗导致肝脏交感神经张力降低和甘油三酯水平升高，而无食欲亢进和体重增加。这些结果表明，中枢细胞瘦素抵抗表现为肝脂肪变性独立 肥胖症。有趣的是，像肥胖一样，饥饿也会诱导严重的肝脂肪变性。这通常被认为是由于白色脂肪组织的动员导致游离脂肪酸向肝脏的输送增加所致。在这个建议中，我们将测试的假设，瘦素水平的下降，饥饿期间所需的肝脂肪变性的发展。我们 将评估饥饿时肝脏脂质储存的增加是否有助于确保肝脏持续产生能量以满足肝外组织的能量需求。我们进一步提出，Agouti相关蛋白（AGRP）是一个下游效应瘦素的行动对肝脏脂质代谢在饥饿，我们将定义AGRP的影响的神经元回路。最后，我们将探讨野生型动物中AGRP的拮抗作用是否会减轻饮食诱导的肥胖症中的肝脂肪变性。这项研究，如果成功的话，将建立饥饿诱导的肝脏脂肪变性不仅仅是一个被动的过程所造成的增加游离脂肪酸流量的肝脏，因为通常认为，而是一个整体的适应性调节瘦素，以确保能源供应在长期的食物匮乏的组成部分。这种机制也可能在饮食诱导的肥胖症中起作用，因为由于瘦素抗性导致的瘦素信号传导的损伤被大脑感知为负能量平衡的状态，触发与饥饿中类似的适应性反应并导致非酒精性脂肪肝疾病。

DESCRIPTION (provided by applicant): Leptin is an adipocyte-derived hormone that circulates at levels proportional to the body's fat mass, which conveys the abundance of peripheral energy stores to the brain. We have previously shown that leptin acts centrally to suppress hepatic lipid content via activation of the sympathetic nervous system; we have further shown that central leptin resistance in the PI3K signaling pathway leads to decreased hepatic sympathetic tone and increased triglyceride levels without hyperphagia and weight gain. These results indicate that central cellular leptin resistance manifests as hepatic steatosis independent of obesity. Interestingly, like obesity, starvation also induces severe hepatic steatosis. This is generally thought to be caused by the increased delivery of free fatty acids to the liver due to th mobilization of the white adipose tissue. In this proposal, we will test the hypothesis that the decline of leptin levels during starvation is required for the development of hepatic steatosis. We will evaluate whether the increase of hepatic lipid stores in starvation serves to ensure sustained energy production from the liver to meet the energy demands of extra-hepatic tissues. We further propose that Agouti-related protein (AGRP) is a downstream effector of leptin's action on hepatic lipid metabolism in starvation, and we will define the neuronal circuitry underlying AGRP's effects. Finally, we will explore whether antagonism of AGRP in wildtype animals would alleviate hepatic steatosis in diet-induced obesity. This study, if successful, will establish that starvation-induced liver steatosis is not just a passive process caused by increased free fatty acid flux to the liver, as commonly thought, but rather an integral component of the overall adaptive regulation by leptin to ensure energy availability during long period of food deprivation. This mechanism may also operate in diet-induced obesity in that impairment of leptin signaling due to leptin resistance is perceived by the brain as a state of negative energy balance, triggering similar adaptive responses as in starvation and contributing to non-alcoholic fatty liver diseases.