Identifying metabolic mechanisms that regulate appetite and foodintake

识别调节食欲和食物摄入的代谢机制

• 批准号: 10309083
• 负责人: T Keith Blackwell
• 金额: $ 21.25万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10309083
• 关键词: 5' -AMP-activated protein kinase; Aging; Animal Model; Animals; Appetite Regulation; Area; Behavior; Behavior Control; Biological; CREB1 gene; CRF receptor type 1; Caenorhabditis elegans; Catabolic Process; Consumption; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Desire for food; Eating; Event; Exhibits; Feeding behaviors; Food; Food Aversion; Future; Genes; Genetic Transcription; Growth; Homeostasis; Hunger; Individual; Ingestion; Intermittent fasting; Link; Lipids; Longevity; Mediating; Metabolic; Metabolism; Methods; Modeling; Molecular; Monounsaturated Fatty Acids; Neurons; Nutritional; Obesity; Oleic Acids; Organism; Pathogenicity; Pathway interactions; Pattern; Perception; Peripheral; Phosphotransferases; Protein Kinase; Pump; Regulation; Research; Satiation; Serotonin; Signal Transduction; Supplementation; Testing; Tissues; Work; anti aging; behavior influence; dietary restriction; feeding; follow-up; food consumption; food quality; high throughput screening; innovation; insight; interest; knock-down; neuronal circuitry; nutrition; prevent; protein kinase P; response; screening; sensor; transcription factor

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.

项目摘要 了解食欲和食物消耗是如何调节的，对衰老领域至关重要。从 创新的高通量C.在转录因子的筛选中，我们确定了食物的调节因子 消耗（这里称为摄食），我们确定通过敲低CRH-1显著减少摄食， （CREB），其被AMP激活的蛋白激酶（AMPK）抑制。AMPK是一种关键的低能量传感器 它抑制生长信号并促进分解代谢过程，在衰老领域引起了极大的兴趣。 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，这是一个主要的调节进食。 结果表明：（1）在C. elegans AMPK通过在多个组织中起作用来发出“饥饿”信号， 抑制CRH-1。因此，AMPK诱导动物专注于食物（“吃”），但也感知到这一点 食物不足，所以当可能的时候，它会离开去寻找更好的食物，矛盾的是减少食物。 消费(2)这种食物离开行为，我们称之为代谢性食物厌恶，也是由其他因素引发的。 感觉营养不足的状态，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避免 补充，表明OA衍生的脂质信号指示饱腹感或纠正某些代谢 失衡(4)像食物居住一样，代谢性食物厌恶取决于血清素信号，但与 一种行为，使C.线虫会避免食用它认为致病的食物。 在这个探索性的项目中，我们将通过两个目标来测试和扩展这些有趣的模型。目标1 我们将鉴定介导AMPK/CRH-1调节的饥饿行为的信号。我们将探讨AMPK如何 和CRH-1在不同组织中的表达影响进食，并研究了良好的 表征了在其调节食物驻留中的马槟榔素介导的、食物诱导的和其他信号， 厌恶在目标2中，我们将利用靶向筛选和随访分析来阐明代谢 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 筛选以鉴定引起厌恶的代谢紊乱，所述厌恶是或不是OA所抑制的。我们将 调查厌恶是否通常与增加的食物停留配对，并依赖于信号 目的1中确定的机制，如AMPK/CRH-1途径。最后，我们会问， 厌恶事件通过AMPK发出信号，并且开始识别厌恶信号起源的组织。这 该项目将确定将代谢缺陷与特定喂养行为联系起来的机制：食物居住和 寻求更高质量的食物，提供基本的生物学见解， 可能只有在C。优美的