果蝇脂肪体蛋白FIT对进食、睡眠行为的神经调控机制

Nutrition sensing pathway covers the metabolic, endocrine and nervous systems; malfunction of this pathway will trigger metabolic diseases or disorders like obesity and diabetes, may induce neuroethological disorders, like food addiction and insomnia. Thus, seeking for the key messenger factor that conveys the signal of nutritional status to the brain and studying its downstream signal pathways and target brain regions in the nervous system is an important approach to uncover the internal nutrition sensing pathway and its regulatory functions. The applicant’s recent work identified a fat body protein, Female-specific Independent of Transformer (FIT) in flies. Its expression is controlled by the internal amino acid state, and the knock-out mutant exhibits abnormal behaviors in food-intake and sleep; moreover, FIT is involved in the regulation of the insulin signaling in the central nervous system (CNS). This application will systemically investigate FIT function in delivering nutritional signals to the nervous system and the underlying molecular and neurobiological mechanisms in regulating innate behaviors like feeding and sleep, thereby exploring the regulatory function of nutrition sensing pathway on behavior control and its sexual dimorphism from the view of neurobiology. This cross-system integrated study will help to understand comprehensive disorders and diseases related to the metabolic, endocrine and nervous systems, and provide theoretical basis for diagnosis, interference and therapy.

营养感知通路涉及代谢、内分泌和神经等多个系统，其调控异常会引发肥胖、糖尿病等代谢疾患，也可能诱发嗜食症、失眠等神经性行为紊乱。因此，寻找将营养状态信号传递到大脑的关键信使因子，并探索其在神经系统中的下游信号通路和目标脑区，是揭开体内营养感知通路及其调控机体功能的重要途径和方法。申请人近年的工作鉴定出一个果蝇脂肪体蛋白FIT，其表达受体内氨基酸水平调控，突变体表现出进食、睡眠等行为异常，并参与中枢神经系统胰岛素信号的调控。本申请将系统研究FIT蛋白在营养信号向神经系统传递中的功能，及其调控进食、睡眠本能行为的神经分子机制，从神经生物学角度探索营养感知通路在行为调控和性别差异中的作用。此跨系统的整合研究将有助于理解代谢-内分泌-神经相关的综合性紊乱和疾病，并为诊断、干预及治疗方法提供理论依据。

营养感知通路对于动物的生存和健康非常重要。作为三大营养源之一，蛋白质具有最强的饱腹感和抑制进食的作用，而其神经分子机制并不清晰。我们早期的研究找到了蛋白质营养感知的关键因子FIT，本项目按计划对其进行了系统深入的研究。首先，我们解析了fit的分子表达调控特性，它表达在成蝇的脂肪体中，高蛋白营养信号通过TOR通路诱导其表达。其次，我们检验了FIT信号对于蛋白摄入引起的进食抑制是充分必要的，而且具有营养特异性。我们进一步探究了FIT发挥功能的分子、细胞、神经机制，发现它是一个分泌因子，可以将高蛋白营养信号跨组织传递至神经系统，通过调节脑内类胰岛素肽DILP2的分泌来调控进食行为。我们还对FIT的潜在受体进行了行为学筛选，并得到了候选GPCR基因。相关结果在Nat Commun等发表四篇学术论文，并在GRC和EMBO等国际会议上多次报告交流。本项目预期目标均已圆满完成，并为后续工作的开展提供了重要线索。