Identifying metabolic mechanisms that regulate appetite and foodintake

项目摘要 了解食欲和食物消费是如何调节的，这对老龄化领域至关重要。从一个 创新的高通量线虫转录因子的筛选，我们在其中确定了食物的调节因子 消耗(这里称为摄食)，我们确定通过敲除CRH-1可以显著减少摄食 (CREB)，它被AMP激活的蛋白激酶(AMPK)抑制。AMPK是一种关键的低能量传感器 抑制生长信号和促进分解代谢过程的状态，在衰老领域引起极大兴趣。 我们令人兴奋的初步发现表明，AMPK和某些其他代谢信号调节 以意想不到的方式进食，并揭示了一种新的行为模式，这是进食的主要调节因素。 他们认为：(1)在线虫体内，AMPK通过作用于多个组织并部分通过 抑制CRH-1。AMPK因此诱导动物停留在食物上(“吃”)，但也感觉到这 食物不足，所以在可能的情况下，它们会离开去寻找更好的食物，自相矛盾地减少食物 消费。(2)这种离开食物的行为，我们称之为代谢性食物厌恶，也是由其他因素引发的 感觉到营养不足的状况，包括缺乏单不饱和脂肪酸(MUFA)油酸 (OA)或其他特定的FA。(3)在大多数情况下，但不是所有情况下，代谢性食物厌恶可以通过OA来避免 补充，表明OA衍生的脂质信号表明饱腹感或纠正某些新陈代谢 不平衡。(4)像食物居住一样，新陈代谢食物厌恶依赖于5-羟色胺信号，但与 线虫避开它认为是致病的食物的行为。 在这个探索性项目中，我们将通过两个目标来测试和扩展这些有趣的模型。在目标1中 我们将确定介导AMPK/CRH-1调节饥饿行为的信号。我们将探索AMPK如何 CRH-1在不同组织中的表达影响摄食，并研究井- 表征了5-羟色胺介导的、食物诱导的和其他信号在它们调节食物栖息和 厌恶。在目标2中，我们将利用有针对性的筛查和后续分析来阐明代谢 调节食物厌恶和居住的机制。我们将完成一个中等规模的基因敲除 筛选，以确定引起厌恶的代谢扰动，这是或不能被OA抑制的。我们会 研究厌恶是否通常伴随着食物储备的增加，并依赖于信号 目标1中确定的机制，AMPK/CRH-1途径也是如此。最后，我们会问是否有些人 厌恶事件通过AMPK发出信号，并开始识别产生厌恶信号的组织。这 该项目将确定将代谢缺陷与特定摄食行为联系起来的机制：食物栖息地和 寻求更高质量的食物，以清晰的水平提供基本的生物学见解 只有在线虫中才有可能。

Project Summary Understanding how appetite and food consumption are regulated is critical to the aging field. From an innovative high-throughput C. elegans screen of transcription factors, in which we identified regulators of food consumption (here termed feeding), we determined that feeding is dramatically reduced by knockdown of crh-1 (CREB), which is inhibited by AMP-activated protein kinase (AMPK). AMPK is a key sensor of low energy states that inhibits growth signals and promotes catabolic processes and is of great interest in the aging field. Our exciting preliminary findings indicate that AMPK and certain other metabolic signals regulate feeding in unexpected ways and have revealed a new behavior pattern that is a major regulator of feeding. They suggest that: (1) In C. elegans AMPK signals “hunger” by acting in multiple tissues and in part by inhibiting CRH-1. AMPK thereby induces the animal to dwell on food (“eating”) but also to perceive that this food is inadequate, so that when possible it will leave in search of better food, paradoxically reducing food consumption. (2) This food-leaving behavior, which we term metabolic food aversion, is also triggered by other states of perceived nutritional inadequacy, including lack of the mono-unsaturated fatty acid (MUFA) oleic acid (OA) or other specific FAs. (3) In most but not all cases metabolic food aversion can be averted by OA supplementation, suggesting that an OA-derived lipid signal indicates satiety or corrects certain metabolic imbalances. (4) Like food dwelling, metabolic food aversion depends upon serotonin signaling, but is related to a behavior whereby C. elegans avoids food that it perceives to be pathogenic. In this exploratory project we will test and extend these intriguing models through two Aims. In Aim 1 we will identify signals that mediate AMPK/CRH-1-regulated hunger behaviors. We will explore how AMPK and CRH-1 expression in different tissues influences feeding and investigate the involvement of well- characterized serotonin-mediated, food-induced, and other signals in their regulation of food dwelling and aversion. In Aim 2, we will leverage targeted screening and follow-up analyses to elucidate metabolic mechanisms that regulate food aversion and dwelling. We will complete a medium-scale gene knockdown screen to identify metabolic perturbations that induce aversion that is or is not suppressible by OA. We will investigate whether aversion is generally paired with increased food dwelling and is dependent upon signaling mechanisms identified in Aim 1, as is true for the AMPK/CRH-1 pathway. Finally, we will ask whether some aversion events signal through AMPK and begin to identify tissues from which aversion signals originate. This project will identify mechanisms that link metabolic deficits to specific feeding behaviors: food dwelling and seeking of higher quality food, providing fundamental biological insights at a level of clarity that would be possible only in C. elegans.