Protein Tyrosine Phosphatase Receptor δ Serves As the Orexigenic Asprosin Receptor

Authors

Ila Mishra
Wei Rose Xie
Juan C Bournat
Yang He
Chunmei Wang
Elizabeth Sabath Silva
Hailan Liu
Zhiqiang Ku
Yinghua Chen
Bernadette O Erokwu
Peilin Jia
Zhongming Zhao
Zhiqiang An
Chris A Flask
Yanlin He
Yong Xu
Atul R Chopra

Publication Date

4-5-2022

Journal

Cell Metabolism

Abstract

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.

Keywords

Agouti-Related Protein, Animals, Fibrillin-1, Glucose, Ligands, Mice, Obesity, Peptide Fragments, Peptide Hormones, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Asprosin, receptor, Ptprd, AgRP, metabolism, obesity

DOI

10.1016/j.cmet.2022.02.012

PMID

35298903

PMCID

PMC8986618

PubMedCentral® Posted Date

4-5-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes