Protein tyrosine phosphatase receptor d serves as the orexigenic asprosin receptor

Authors: MISHRA, IIA - Harrington Discovery Institute; XIE, WEI ROSE - Harrington Discovery Institute; BOURNAT, JUAN - Baylor College Of Medicine; HE, YANG - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); SILVA, ELIZABETH - Harrington Discovery Institute; LIU, HAILAN - Children'S Nutrition Research Center (CNRC); KU, ZHIQIANG - University Of Texas Health Science Center; CHEN, YINGHUA - Case Western Reserve University (CWRU); EROKWU, BERNADETTE - Case Western Reserve University (CWRU); JIA, PEILIN - University Of Texas Health Science Center; ZHAO, ZHONGMING - University Of Texas Health Science Center; AN, ZHIQIANG - University Of Texas Health Science Center; FLASK, CHRIS - Case Western Reserve University (CWRU); HE, YANLIN - Louisana State University; XU, YONG - Children'S Nutrition Research Center (CNRC); CHOPRA, ATUL - Case Western Reserve University (CWRU)

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/22/2022
Publication Date: 3/16/2022
Citation: Mishra, I., Xie, W., Bournat, J.C., He, Y., Wang, C., Silva, E., Liu, H., Ku, Z., Chen, Y., Erokwu, B.O., Jia, P., Zhao, Z., An, Z., Flask, C.A., He, Y., Xu, Y., Chopra, A.R. 2022. Protein tyrosine phosphatase receptor d serves as the orexigenic asprosin receptor. Cell Metabolism. 34(4):549-563. https://doi.org/10.1016/j.cmet.2022.02.012.
DOI: https://doi.org/10.1016/j.cmet.2022.02.012

Interpretive Summary: Asprosin is a hormone that is produced when a person fasts, and it stimulates the production of glucose and increases appetite. The liver receptor for asprosin that affects glucose production has been identified as the olfactory receptor Olfr734. However, the receptor responsible for asprosin's appetite-inducing function was previously unknown. A study has now identified the protein tyrosine phosphatase receptor (Ptprd) as the receptor for asprosin's appetite-inducing effects. Asprosin acts as a high-affinity Ptprd ligand in hypothalamic AgRP neurons, regulating their activity in a cell-autonomous manner. Genetic deletion of Ptprd in mice results in a strong loss of appetite, leanness, and an inability to respond to the appetite-inducing effects of asprosin. The study suggests that targeting Ptprd could be a new approach for developing anti-obesity treatments.

Technical 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 d (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.