Feeding regulation by ASB4

项目总结/摘要 大多数常见形式的肥胖的遗传基础是多基因的，突出了相互作用的重要性 不同的基因变异在体重调节中的作用。事实上，大规模的GWAS研究已经发现， 越来越多的基因变异与人类肥胖有关。尽管取得了这些进展， 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， 仍然知之甚少。我们最近发现了锚蛋白重复序列和SOCS盒包含4（ASB 4），一个基因， 多项GWAS研究表明，它与人类肥胖有关，是饱腹感的重要调节因素，特别是在 食物匮乏的时期。Asb 4的表达受营养状况的调节，对瘦素有反应 和刺豚鼠相关蛋白质的相互作用，使ASB 4能够感知身体能量储备的变化。 我们发现，ASB 4缺乏会导致高强度喂养期间的膳食量和食物摄入量增加， 例如再喂养。我们还发现ASB 4是降钙素受体（CalcR）表达所必需的， 鲑鱼降钙素的厌食作用，一种有效的钙受体配体。总之，这些发现有力地表明， ASB 4对人类和小鼠的代谢控制很重要，并且它是膳食的重要调节剂， 尺寸本R 01应用的目标是确定ASB 4发挥其代谢作用的机制。 方面的影响.我们将确定ASB 4神经元亚群，控制膳食大小和食物摄入量。我们将评估 如果ASB 4在饱腹感控制中的重要性在间歇性禁食下表现出来，那么促进 大的饮食消费。由于ASB 4在小鼠和人类之间高度保守，并且与肥胖有关， 通过GWAS的研究，本研究将为ASB 4如何调节膳食量和食物提供机理性的见解 摄入人体内。

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.