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，其循环水平与身体的脂肪量成正比，将丰富的外周能量储存传递给大脑。我们之前已经证明瘦素通过激活交感神经系统来抑制肝脏脂质含量；我们进一步表明，PI3K信号通路中的中枢性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，但不会导致贪食和体重增加。这些结果表明，中枢细胞瘦素抵抗表现为肝脂肪变性独立

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.