Identifying metabolic mechanisms that regulate appetite and foodintake

识别调节食欲和食物摄入的代谢机制

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目概要了解食欲和食物消耗是如何调节的对于老龄化领域至关重要。创新的高通量线虫转录因子筛选，其中我们确定了食物的调节因子消耗（这里称为喂养），我们确定通过击倒crh-1可以显着减少喂养 (CREB) 被 AMP 激活蛋白激酶 (AMPK) 抑制，是低能量的关键传感器。表明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，这是进食的主要调节因素。他们认为：（1）在线虫中，AMPK 通过作用于多个组织来发出“饥饿”信号，部分通过抑制 CRH-1 从而诱导动物专注于食物（“吃”），同时也感知到这一点。食物不足，因此在可能的情况下它会离开去寻找更好的食物，矛盾的是减少食物 (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。认为营养不足的状态，包括缺乏单不饱和脂肪酸 (MUFA) 油酸 (OA) 或其他特定 FA (3) 在大多数但并非所有情况下，OA 可以避免代谢性食物厌恶。补充，表明 OA 衍生的脂质信号表明饱腹感或纠正某些代谢 (4) 与食物居住一样，代谢性食物厌恶取决于血清素信号，但与食物相关。线虫避免食用它认为致病的食物的行为。在这个探索性项目中，我们将通过目标 1 的两个目标来测试和扩展这些有趣的模型。我们将识别介导 AMPK/CRH-1 调节饥饿行为的信号我们将探索 AMPK 如何发挥作用。不同组织中的 CRH-1 表达影响摄食，并研究良好的参与情况表征了血清素介导的、食物诱导的和其他信号在食物居住和调节中的作用在目标 2 中，我们将利用有针对性的筛查和后续分析来阐明代谢。我们将完成中等规模的基因敲除。筛选以确定引起厌恶的代谢扰动，这些厌恶是否可以被 OA 抑制。研究厌恶是否通常与食物停留时间的增加相伴，并且是否依赖于信号传导目标 1 中确定的机制，对于 AMPK/CRH-1 途径也是如此。最后，我们会问是否有一些机制。厌恶事件通过 AMPK 发出信号，并开始识别厌恶信号的来源组织。该项目将确定将代谢缺陷与特定进食行为联系起来的机制：食物居住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仅可能存在于秀丽隐杆线虫中。