The CNS Receptor For Asprosin

项目总结 Asprosin是一种新近发现的禁食诱导激素，它能刺激肝脏葡萄糖的产生和 胃口。血浆天冬氨酸氨基转移酶穿过血脑屏障，直接激活嗜氧性AgRP神经元， 导致下游厌食性POMC神经元抑制，以GABA依赖的方式。这种阿司匹林- 一连串的事件会刺激食欲，并促使肥胖和体重增加。 人类Asprosin的遗传缺陷导致新生儿进展性综合征(NPS)，其特征是低 食欲和极度瘦弱，这一结果被携带类似基因突变的小鼠模仿。肥胖的人和老鼠 用单抗显示病理性循环Asprosin水平升高和血浆Asprosin耗竭 抗体除了改善小鼠的血糖水平外，还能降低小鼠的食欲和体重。因此， Asprosin除了执行生糖功能外，还是一种促食欲激素，也是抗Asprosin 抗体显示出作为抗肥胖剂的治疗潜力。 上述观察引出的一个中心问题是：天冬氨酸细胞表面的特性是什么？ 受体？最近，通过对小鼠大脑的无偏质谱分析，我们确定了一个候选 天冬氨酸受体(AR)可能是一种脑部天冬氨酸受体。AR在AgRP神经元中强烈表达，但 在肝脏中不表达。相反，最近发现的肝脏天冬氨酸受体(OLF734)，而 在肝脏中高表达，在AgRP神经元中不表达，Olfr734-/-小鼠不显示 消瘦或食欲下降。因此，Olfr734不能解释Asprosin对AgRP神经元的刺激作用 和食欲。除了确认AR是阿司匹林的结合伙伴外，我们还介绍了初步研究 证明AR在Asprosin介导的AgRP神经元激活、食欲刺激和免疫抑制中的必要性 保持体重。该提案寻求在这些初步结果的基础上确定 AR在脑内作为天冬氨酸受体的作用。 我们试图在以下三个目标内做到这一点：1)确定阿司匹林促食欲素AR的必要性 效果2)验证AR可溶性配体结合域对代谢综合征的疗效3)确定 天冬氨酸神经化降低食欲、体重和相互作用的分子机制 有瘦素信号。在完成这些目标后，我们期望最终验证AR作为大脑受体的作用 通过对阿司匹林的必要性、可药性、功能和体内机制的探讨，对阿司匹林进行了初步研究。

PROJECT SUMMARY Asprosin is a recently discovered, fasting-induced hormone that stimulates hepatic glucose production and appetite. Plasma asprosin crosses the blood-brain-barrier and directly activates orexigenic AgRP neurons, resulting in downstream anorexigenic POMC neuron inhibition, in a GABA-dependent manner. This asprosin- mediated chain of events leads to appetite stimulation and a drive to accumulate adiposity and body weight. Genetic deficiency of asprosin in humans results in Neonatal Progeroid Syndrome (NPS), characterized by low appetite and extreme leanness, a result mimicked by mice carrying similar mutations. Obese humans and mice display pathologically elevated circulating asprosin levels, and depletion of plasma asprosin using monoclonal antibodies reduces appetite and body weight in such mice, in addition to improving their glycemic profile. Thus, asprosin, in addition to performing a glucogenic function, is an orexigenic hormone, and anti-asprosin antibodies show therapeutic potential as anti-obesity agents. A central question the above observations have led to is – what is the identity of the asprosin cell-surface receptor? Recently, through unbiased mass spectrometry on the mouse brain we identified a candidate asprosin receptor (AR) as a putative brain receptor for asprosin. AR is robustly expressed in AgRP neurons but not expressed in the liver. Conversely, the recently discovered liver receptor for asprosin (OLF734), while being highly expressed in the liver, is not expressed in AgRP neurons and Olfr734-/- mice do not display leanness or reduced appetite. Thus, Olfr734 cannot account for asprosin’s stimulatory effect on AgRP neurons and appetite. Besides confirming AR as a binding partner for asprosin, we present preliminary studies demonstrating the necessity of AR for asprosin mediated AgRP neuron activation, appetite stimulation and body weight maintenance. This proposal seeks to build on these preliminary results to determine the contribution of AR as an asprosin receptor in the brain. We seek to do so within the following 3 aims: 1) Determine the necessity of AR for asprosin’s orexigenic effects 2) Validate the AR soluble ligand binding domain for efficacy against metabolic syndrome 3) Determine the molecular mechanisms by which asprosin neuralization reduces appetite and body weight and interplay with leptin signaling. At the completion of these aims we expect to definitively validate AR as the brain receptor for asprosin through an exploration of necessity, druggability, function and in vivo mechanism.