Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor

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

doi:10.1016/j.cmet.2022.02.012

Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor

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

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English
Pages (from-to)	549-563.e8
Journal	Cell Metabolism
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2022.02.012
State	Published - Apr 5 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Funding

We thank Andrew Pieper, Seth Field, and members of the Chopra lab for helpful suggestions and critical reading of the manuscript. This work was supported by the NIDDK (DK102529 and DK118290). Formal analysis, I.M.; investigation, I.M. W.R.X. J.C.B. Y.H. C.W. E.S.S. H.L. Z.K. Y.C. and B.O.E.; methodology, I.M. and W.R.X.; writing—original draft, I.M.; analysis, P.J.; supervision, Z.Z. Z.A. C.A.F. Y.X. and A.R.C.; resources, Z.A. C.A.F. Y.X. and A.R.C.; investigation, Y.H.; conceptualization, A.R.C.; funding acquisition, A.R.C.; writing—review & editing, A.R.C. Atul Chopra has been awarded asprosin-related patents and is a co-founder, director, and officer of Vizigen, Inc. and Aceragen, Inc. and holds equity in both companies. The other authors declare no competing interests. We thank Andrew Pieper, Seth Field, and members of the Chopra lab for helpful suggestions and critical reading of the manuscript. This work was supported by the NIDDK ( DK102529 and DK118290 ).

Funders	Funder number
A.R.C. A.R.C.
Andrew Pieper
Seth Field
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK125403, DK118290, DK102529
National Institute of Diabetes and Digestive and Kidney Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AgRP
Ptprd
appetite
asprosin
hypothalamus
metabolism
obesity
receptor

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2022.02.012

Cite this

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title = "Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor",

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 = "AgRP, Ptprd, appetite, asprosin, hypothalamus, metabolism, obesity, receptor",

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

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doi = "10.1016/j.cmet.2022.02.012",

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AU - Mishra, Ila

AU - Xie, Wei Rose

AU - Bournat, Juan C.

AU - He, Yang

AU - Wang, Chunmei

AU - Silva, Elizabeth Sabath

AU - Liu, Hailan

AU - Ku, Zhiqiang

AU - Chen, Yinghua

AU - Erokwu, Bernadette O.

AU - Jia, Peilin

AU - Zhao, Zhongming

AU - An, Zhiqiang

AU - Flask, Chris A.

AU - He, Yanlin

AU - Xu, Yong

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AB - 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.

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KW - appetite

KW - asprosin

KW - hypothalamus

KW - metabolism

KW - obesity

KW - receptor

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Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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