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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.

SUBMITTER: Mishra I

PROVIDER: S-EPMC8986618 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor.

Mishra Ila I Xie Wei Rose WR Bournat Juan C JC He Yang Y Wang Chunmei C Silva Elizabeth Sabath ES Liu Hailan H Ku Zhiqiang Z Chen Yinghua Y Erokwu Bernadette O BO Jia Peilin P Zhao Zhongming Z An Zhiqiang Z Flask Chris A CA He Yanlin Y Xu Yong Y Chopra Atul R AR

Cell metabolism 20220316 4

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 ...[more]

PMID: 35298903

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Project description:Background & Aims: Protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including HCV infection. To identify hepatic pathways responsive to PTPRD function and their role in non-viral liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Healthy patients were classified according to hepatic PTPRD expression and transcriptomic analysis was performed to identify signaling pathways associated with low PTPRD levels. We combined an animal model for metabolic dysfunction-associated steatohepatitis (MASH) with genetically impaired PTPRD expression (Ptprd+/-) to assess its impact on the liver transcriptome and metabolic function. Identified pathways were validated by perturbation studies in primary human hepatocytes and differentiated HepaRG cells. Substrate specificity was validated by pull-down assay. The clinical relevance was explored in a cohort of patients with fatty liver disease by ranking individuals according to hepatic PTPRD expression and analyzing its association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice, PTPRD levels associated with hepatic glucose/lipid metabolism and peroxisomal function. Hepatic PTPRD expression is impaired in metabolic liver disease. Moreover, we revealed PTPRD as a STAT3 phosphatase in the liver, which is a regulator of peroxisomal function. Silencing of STAT3 in HepaRG cells treated with free-fatty acids was able to rescue the expression of genes implicated in lipid metabolism. During MASH, low hepatic PTPRD led to increased liver steatosis in the Ptprd+/- animals and pronounced unfolded protein response, which impacts insulin signaling. Silencing of PTPRD in PHH blunted insulin-induced AKT phosphorylation. In line with this, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggest an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic liver disease.

Project description:Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. Little is known about the protein-tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells, or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable 32D myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. In particular, the sites pTyr-589, pTyr-591, and pTyr-842 involved in the FLT3 ligand (FL)-mediated activation of FLT3 were hyperphosphorylated the most. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Direct interaction of DEP-1 and FLT3 was demonstrated by "substrate trapping" experiments showing association of DEP-1 D1205A or C1239S mutant proteins with FLT3 by co-immunoprecipitation. Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro. Enhanced FLT3 phosphorylation in DEP-1-depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Stable overexpression of DEP-1 in 32D cells and transient overexpression with FLT3 in HEK293 cells resulted in reduction of FL-mediated FLT3 signaling activity. Furthermore, FL-stimulated colony formation of 32D cells expressing FLT3 in methylcellulose was induced in response to shRNA-mediated DEP-1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL stimulation but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

Dataset Information

Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor.

Publications

Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor.

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