Feeding regulation by ASB4

项目摘要/摘要 大多数常见肥胖症的遗传基础是多基因的，突出了相互作用的重要性 在体重调节的不同遗传变异中。事实上，大规模的全球气候变化研究已经确定 越来越多的与人类肥胖有关的基因变异。尽管有这些进步，但 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因子相互作用 人们对此仍知之甚少。我们最近发现了Ankyrin Repeat和SoCS Box包含4(ASB4)，一个可以 被多项GWAS研究表明与人类肥胖有关，作为饱腹感的重要调节因素，尤其是在 食物匮乏的时期。Asb4的表达受营养状态的调节，对瘦素有反应 和刺鼠相关蛋白的相互作用，使ASB4能够感知人体能量储备的变化。 我们发现，缺乏ASB4会导致紧张喂食期间的食量和食物摄入量增加， 比如重新进食。我们还发现，ASB4是降钙素受体(CalcR)表达所必需的，并且 鲑鱼降钙素，一种有效的钙调蛋白配体的厌食作用。总而言之，这些发现强烈表明 ASB4对人类和小鼠的新陈代谢控制很重要，它是膳食的重要调节剂 尺码。此R01应用程序的目标是确定ASB4发挥其代谢作用的机制 效果。我们将确定控制进食量和食物摄入量的ASB4神经元亚群。我们将评估 如果ASB4在控制饱腹感方面的重要性在间歇禁食下表现出来，一种促进 大餐的消费。因为ASB4在老鼠和人类之间高度保守，并与肥胖有关 通过GWAS的研究，这项研究将提供ASB4如何调节膳食大小和食物的机械性洞察 人体摄入量。

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.