Roles of Drosophila NPY-and Insulin-like Activities in Food Response

描述（申请人提供）：本实验室最近的研究提供了直接证据，证明果蝇是研究进食行为控制和饮食失调的分子、细胞和神经基础的合适遗传模型。果蝇神经肽F （Drosophila neuropeptide F， NPF）是哺乳动物神经肽F的果蝇同源物，在调节饥饿驱动的觅食和摄食行为中起重要作用。在npf缺陷果蝇和npy敲除小鼠之间观察到相似的行为表型：两种动物在基线摄食和体重控制方面都是正常的，但在剥夺状态下表现出摄食不足；npf缺陷果蝇和NPY基因敲除小鼠对乙醇镇静的急性敏感性也有所下降。最近，我们已经获得了类似于哺乳动物胰岛素的证据，果蝇胰岛素样肽（dilp）通过作用于不同的神经网络，包括npy样神经通路，来抑制摄食反应。例如，dilp似乎通过胰岛素样受体(lnR)/核糖体S6激酶（S6K）途径直接抑制NPFR1神经元的信号活性。综上所述，我们的研究结果强烈表明，果蝇和哺乳动物之间的觅食和摄食行为调节的信号机制在很大程度上是保守的。拟议的研究旨在确定和表征对饥饿驱动行为至关重要的其他基因、分子和神经通路。我们对调节饥饿反应不同方面的基因和神经元特别感兴趣，如增强食物寻找，主动摄入不喜欢的食物，增加摄食率。该应用的具体目的包括：1)分析NPFR1神经元调控饥饿觅食的基因和分子途径；2) DILP神经元调控饥饿驱动行为的基因和分子通路分析；3) DILP/NPFR1神经元介导的饥饿反应关键基因的功能获得筛选。这些研究的结果可能为包括哺乳动物在内的多种生物的饥饿调节食物反应的遗传和神经因素如何起作用提供一般性见解。

DESCRIPTION (provided by applicant): The recent research from this laboratory provides direct evidence that Drosophila is a suitable genetic model for studying molecular, cellular and neural basis of feeding behavioral control and eating disorders. We have shown that Drosophila neuropeptide F (NPF), the fly homologue of mammalian NPY, plays an important role in regulating hunger-driven foraging and feeding behaviors. Parallel behavioral phenotypes have been observed between NPF-deficient flies and NPY-knockout mice: both animals were normal in baseline feeding and body weight control but displayed feeding deficits in the deprived state; NPF-deficient flies and NPY knockout mice also displayed decreased acute sensitivity to ethanol sedation. More recently, we have obtained evidence that analogous to mammalian insulin, Drosophila insulin-like peptides (DILPs) suppress feeding response by acting oh different neuronal networks including the NPY-like neuronal pathway. For example, DILPs appear to directly inhibit the signaling activity of NPFR1 neurons through the insulin-like receptor (lnR)/ribosomal S6 kinase (S6K) pathway. Taken together, our findings strongly suggest that signaling mechanisms for the regulation of foraging and feeding behaviors are largely conserved between flies and mammals. The proposed research aims to identify and characterize additional genes and molecular and neuronal pathways critical for hunger-driven behaviors. We are particularly interested in genes and neurons that differentially regulate distinct aspects of hunger response such as enhanced food seeking, motivated intake of less-preferred foods, and increased ingestion rate. The specific aims of this application include: 1) Analysis of genes and molecular pathways underlying the regulation of hunger-motivated foraging by NPFR1 neurons; 2) Analysis of genes and molecular pathways underlying the regulation of hunger-driven behaviors by DILP neurons; 3) Gain-of-function screen for genes critical for DILP/NPFR1 neuron-mediated hunger response. The results from these studies may provide general insights into how genetic and neural factors contribute to hunger regulation of food response in diverse organisms including mammals.