Harrington Discovery Institute, Cleveland, OH, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Cell Metab. 2022 Apr 5;34(4):549-563.e8. doi: 10.1016/j.cmet.2022.02.012. Epub 2022 Mar 16.
Asprosin is a fasting-induced glucogenic and centrally acting orexigenic hormone. The olfactory receptor Olfr734 is known to be the hepatic receptor for asprosin that mediates its effects on glucose production, but the receptor for asprosin's orexigenic function has been unclear. Here, we have identified protein tyrosine phosphatase receptor δ (Ptprd) as the orexigenic receptor for asprosin. Asprosin functions as a high-affinity Ptprd ligand in hypothalamic AgRP neurons, regulating the activity of this circuit in a cell-autonomous manner. Genetic ablation of Ptprd results in a strong loss of appetite, leanness, and an inability to respond to the orexigenic effects of asprosin. Ablation of Ptprd specifically in AgRP neurons causes resistance to diet-induced obesity. Introduction of the soluble Ptprd ligand-binding domain in the circulation of mice suppresses appetite and blood glucose levels by sequestering plasma asprosin. Identification of Ptprd as the orexigenic asprosin receptor creates a new avenue for the development of anti-obesity therapeutics.
脑肠肽激素 Asprosin 是一种饥饿诱导的产糖和中枢作用的食欲素。已知嗅觉受体 Olfr734 是 Asprosin 的肝受体，介导其对葡萄糖生成的作用，但 Asprosin 的食欲素功能的受体尚不清楚。在这里，我们确定蛋白酪氨酸磷酸酶受体 δ（Ptprd）是 Asprosin 的食欲素受体。Asprosin 在下丘脑 AgRP 神经元中作为高亲和力 Ptprd 配体发挥作用，以细胞自主的方式调节该回路的活性。Ptprd 的基因缺失会导致强烈的食欲减退、消瘦和无法对 Asprosin 的食欲素作用产生反应。特异性在 AgRP 神经元中缺失 Ptprd 会导致对饮食诱导肥胖的抵抗。将可溶性 Ptprd 配体结合域引入小鼠循环中，通过隔离血浆中的 Asprosin 来抑制食欲和血糖水平。鉴定出 Ptprd 是食欲素的 Asprosin 受体，为开发抗肥胖治疗药物开辟了新途径。
