Feeding regulation by ASB4

ASB4 的饲喂调节

• 批准号: 10886884
• 负责人: Allison W Xu
• 金额: $ 16.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886884
• 关键词: ART protein; Acute; Amino Acid Sequence; Animals; Ankyrin Repeat; Appetite Depressants; Area; Attenuated; Binding; Binge Eating; Body Weight; Brain; Calcitonin; Calcitonin Receptor; Cells; Cephalic; Consumption; Down-Regulation; Eating; Evolution; Fasting; Feeding Patterns; Food; Food deprivation (experimental); Gene Targeting; Genes; Genetic; Goals; Health; Human; Hyperphagia; Hypothalamic structure; IRS4 gene; Injections; Intermittent fasting; Leptin; Leptin deficiency; Ligands; Link; Mediating; Metabolic; Metabolic Control; Metabolic hormone; Metabolism; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Opsin; Persons; Phenotype; Photophobia; Play; Prosencephalon; Protein Deficiency; Regulation; Resistance; Role; Salmon; Satiation; Structure of nucleus infundibularis hypothalami; Surveys; Weight maintenance regimen; cell type; cognitive function; coping; energy balance; feeding; gene environment interaction; genetic variant; genome wide association study; hindbrain; improved; insight; knock-down; novel; obesity development; optogenetics; sex; ubiquitin-protein ligase

Project Summary/Abstract The genetic basis of most common forms of obesity is polygenic, highlighting the importance of interactions among different genetic variants in body weight regulation. Indeed, large-scale GWAS studies have identified increasing number of genetic variants that are associated with human obesity. Despite these advances, the metabolic functions of these genetic variants and how they interact with key regulators of energy balance are still poorly understood. We recently identified Ankyrin Repeat and SOCS Box Containing 4 (ASB4), a gene that is linked to human obesity by multiple GWAS studies, as an important regulator of satiety especially after period of food deprivation. Expression of Asb4 is modulated by nutritional status, being responsive to leptin and agouti-related protein in a reciprocal fashion, allowing ASB4 to sense changes of body’s energy reserve. We show that ASB4 deficiency leads to increased meal size and food intake during periods of intense feeding, such as refeeding. We also show that ASB4 is required for the expression of calcitonin receptor (CalcR) and the anorectic effects of salmon calcitonin, a potent ligand for CalcR. Together, these findings strongly indicate that ASB4 is important for metabolic control in humans and mice, and that it is an important regulator of meal size. The goal of this R01 application is to determine the mechanisms by which ASB4 exerts its metabolic effects. We will identify ASB4 neuronal subpopulations that control meal size and food intake. We will evaluate if importance of ASB4 in satiety control manifests under intermittent fasting, a feeding pattern that promotes consumption of large meals. As ASB4 is highly conserved between mice and humans and is linked to obesity by GWAS studies, this study will provide mechanistic insight into how ASB4 may regulate meal size and food intake in humans.

项目概要/摘要 最常见肥胖形式的遗传基础是多基因的，凸显了相互作用的重要性 事实上，大规模 GWAS 研究已经确定了体重调节的不同遗传变异。 尽管取得了这些进展，但与人类肥胖相关的遗传变异数量不断增加。 这些遗传变异的代谢功能以及它们如何与能量平衡的关键调节剂相互作用 我们最近发现了锚蛋白重复序列​​和 SOCS Box Containing 4 (ASB4) 基因，该基因 多项 GWAS 研究表明，作为饱腹感的重要调节剂，尤其是在进食后，它与人类肥胖有关。 Asb4 的表达受营养状况调节，对瘦素有反应。 和刺豚鼠相关蛋白以相互的方式存在，使ASB4能够感知身体能量储备的变化。 我们发现，ASB4 缺乏会导致在密集喂养期间膳食量和食物摄入量增加， 例如，我们还表明 ASB4 是降钙素受体 (CalcR) 表达所必需的。 鲑鱼降钙素是 CalcR 的有效配体，这些发现有力地表明了其抑制食欲的作用。 ASB4 对于人类和小鼠的代谢控制很重要，并且是膳食的重要调节剂 该 R01 应用的目标是确定 ASB4 发挥其代谢作用的机制。 我们将确定控制膳食量和食物摄入量的 ASB4 神经元亚群。 如果 ASB4 在饱腹感控制中的重要性在间歇性禁食下显现出来，那么这种喂养模式会促进 由于 ASB4 在小鼠和人类之间高度保守，并且与肥胖有关。 通过 GWAS 研究，这项研究将为 ASB4 如何调节膳食量和食物提供机制见解 人类的摄入量。