Central Regulation of Hepatic Energy Stores

描述(申请人提供)：瘦素是一种脂肪细胞衍生的荷尔蒙，它的循环水平与身体的脂肪质量成正比，它将丰富的外周能量储存传递到大脑。我们之前已经证明，瘦素通过激活交感神经系统发挥中枢作用，抑制肝脏脂质含量；我们进一步证明，PI3K信号通路中的中枢性瘦素抵抗会导致肝脏交感神经张力降低，甘油三酯水平升高，而不会出现吞噬功能亢进和体重增加。这些结果表明，中枢细胞瘦素抵抗表现为不依赖于肝脏脂肪变性。 肥胖症。有趣的是，像肥胖一样，饥饿也会导致严重的肝脏脂肪变性。这通常被认为是由于白色脂肪组织的动员而增加了向肝脏输送游离脂肪酸所致。在这项提案中，我们将检验这样一个假设，即饥饿期间瘦素水平的下降是肝脏脂肪变性发展所必需的。我们 将评估饥饿状态下肝脏脂肪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Agti相关蛋白(AGRP)是瘦素在饥饿状态下对肝脏脂质代谢作用的下游效应因子，并将确定AGRP作用下的神经元回路。最后，我们将探讨AGRP在野生型动物身上的拮抗作用是否会减轻饮食诱导的肥胖中的肝脏脂肪变性。这项研究如果成功，将证明饥饿诱导的肝脏脂肪变性不像人们通常认为的那样，只是由流向肝脏的游离脂肪酸增加引起的一个被动过程，而是瘦素整体适应性调节的一个组成部分，以确保在长时间的食物匮乏期间获得能量。这一机制也可能在饮食诱导的肥胖中起作用，因为瘦素抵抗导致的瘦素信号障碍被大脑视为一种负能量平衡状态，触发与饥饿类似的适应性反应，并导致非酒精性脂肪性肝病。

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.