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 了解如何调节食欲和食物对衰老领域至关重要。从一个 创新的高通量C.秀丽隐杆线虫的转录因子屏幕，其中我们确定了食物的调节剂 消费（在此称为喂养），我们确定CRH-1的敲低可以大大降低喂养 （CREB），它被AMP激活的蛋白激酶（AMPK）抑制。 AMPK是低能的关键传感器 指出的是抑制生长信号并促进分解代谢过程，并且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，这是喂养的主要调节者。 他们建议：（1）在秀丽隐杆线虫中，AMPK在多个时间安排中表明“饥饿”，部分是由 抑制CRH-1。 AMPK因此诱导动物居住在食物上（“吃”），但也认为这是 食物不足 消耗。 （2）我们称这种食物态行为，我们称这种行为的代谢食物厌恶也是由其他人触发的 感知营养不足的状态，包括缺乏单不饱和脂肪酸（MUFA）油酸 （OA）或其他特定的FA。 （3）在大多数但并非所有情况下，代谢食品厌恶都可以通过OA避免 补充，表明OA衍生的脂质信号表示饱腹感或纠正某些代谢 失衡。 （4）像食物居住一样，代谢食物厌恶取决于5-羟色胺信号，但与 秀丽隐杆线虫避免食物认为是致病性的行为。 在这个探索性项目中，我们将通过两个目标测试并扩展这些有趣的模型。在目标1中 我们将确定介导AMPK/CRH-1调节的饥饿行为的信号。我们将探索AMPK 在不同组织中的CRH-1表达会影响进食和研究 在对食物居住和 厌恶。在AIM 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低 屏幕以识别影响OA可补充或不补充的厌恶的代谢扰动。我们将 调查厌恶通常与增加的食物住宅配对，并取决于信号传导 AIM 1中鉴定出的机制，以及对AMPK/CRH-1途径的正确机制。最后，我们会问是否有一些 厌恶事件通过AMPK发出信号，并开始识别厌恶信号起源的组织。这 项目将确定将代谢定义为特定喂养行为的机制：食物居住和 寻求更高质量的食物，提供基本的生物学见解，以清晰的水平 仅在秀丽隐杆线虫中才可能。