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.

项目摘要/摘要 肥胖的最常见形式的遗传基础是多基因，突出了相互作用的重要性 在体重调节的不同遗传变异中。确实，大规模的GWAS研究已经确定 与人肥胖相关的遗传变异数量增加。尽管有这些进步， 这些遗传变异的代谢功能及其与能量平衡的关键调节剂的相互作用是 仍然很了解。我们最近确定了Ankyrin重复和包含4个（ASB4）的SOCS框，该基因是该基因 通过多个GWAS研究与人类肥胖有关，作为饱腹感的重要调节剂，尤其是之后 食物剥夺时期。 ASB4的表达受营养状况调节，对瘦素有反应 和与Agouti相关的蛋白质以相互的方式，使ASB4感觉到人体能量储备的变化。 我们表明，ASB4缺乏会导致进食期间的饮食量增加和食物摄入量增加， 例如参考。我们还表明，降钙素受体（CALCR）和 鲑鱼钙蛋白的厌食作用，鲑鱼是CALCR的潜在配体。这些发现共同表明 ASB4对于人类和小鼠的代谢控制很重要，它是餐的重要调节剂 尺寸。该R01应用程序的目标是确定ASB4执行其代谢的机制 效果。我们将确定控制饮食大小和食物摄入量的ASB4神经元亚群。我们将评估 如果ASB4在饱腹感控制中的重要性在间歇性禁食下表现出来，则可以促进喂食模式 消费大餐。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，本研究将提供有关ASB4如何调节餐大小和食物的机械洞察力 人类摄入量。