高脂饮食促进果蝇和大鼠觅食行为的神经机制研究

Prolonged exposure to high-fat diet (HFD) modulates a series of food-related behaviors which contributes to the increase in the risk of obesity and other metabolic disorders. Although how HFD affects food consumption has been well documented, how HFD affects another critical food intake behavior, food seeking, remains largely uncharacterized. Our previous studies identified a group of neurons expressing adipokinetic hormone receptor (AKHR) as a key regulator of food seeking upon starvation. Our ongoing research suggested that HFD increased the sensitivity of AKHR+ neurons to starvation and enhanced food seeking upon starvation. Based on these results, we propose to further elucidate how HFD modulates food seeking and neuronal activity, which will shed important light on the regulation of food seeking behavior under both physiological and pathological conditions. By using genetic, cell biology, and electrophysiological approaches, we will investigate the cellular mechanism affected by HFD, and examine how these changes regulate the neuronal activity of AKHR+ neurons and hence food seeking behavior. In addition, we will confirm our findings in more complex rodent models. Taken together, our results will provide clues to explore the effect of HFD on food-seeking, and are therefore important to understand the function of food-seeking in metabolic disorders.

高脂食物的过量摄入是导致肥胖的关键原因，一系列与食物相关的神经行为学的改变参与其中，解析这些神经机理将为防治肥胖等疾病提供重要靶点。与进食行为同等重要的是觅食行为，其为动物获取充足的食物来源的提供先决条件。目前，高脂对进食行为影响的研究较为透彻，而对觅食行为有何影响尚不可知。申请人先前的研究在果蝇大脑中鉴定了调控觅食行为的AKHR+神经元，本项目的前期工作强烈提示高脂食物显著增强了饥饿过程中AKHR神经元的活性和觅食行为。我们拟在前期成果的基础上，利用单细胞测序解析AKHR神经元在高脂处理下细胞内信号通路的变化，结合基因操纵技术及电生理记录明确细胞内信号转导途径在AKHR神经元活性调控中的作用，从分子水平阐明AKHR神经元感知高脂及敏感性增强的机制，最终在哺乳动物内检测该机理的保守性。本项目的研究结果将为觅食行为的神经调控机制研究提供新的线索，对解析觅食行为在代谢失衡中的作用具有重要意义。

高脂饮食会影响中枢神经系统对进食相关行为的调控，这是一系列代谢病发生发展的原因之一。我们先前在果蝇中发现章鱼胺神经元调控饥饿诱导的觅食行为，本项目研究发现高脂饮食会显著增强这一行为。高脂饮食上调了章鱼胺神经元表面脂动员激素受体AKHR的表达量，从而使其对饿激素AKH更敏感。当进食高脂食物后，过量的脂质在脂蛋白LTP和脂蛋白受体LpR1的帮助下进入章鱼胺神经元，进而抑制了AKHR蛋白的自噬性降解。综上，我们的结果将高脂饮食、神经元自噬和觅食行为密切联系起来，揭示了特殊饮食在神经元重塑和代谢疾病发展中的作用。

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