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Ptprf is the conserved receptor for Asprosin’s glucogenic effects in vertebrates

ABSTRACT: Asprosin, a fasting-induced glucogenic hormone, plays a crucial role in maintaining glucose homeostasis; however, its receptor remains elusive. This study identifies protein tyrosine phosphatase receptor F (Ptprf) as the receptor mediating Asprosin's metabolic functions. Using zebrafish models, we demonstrate the evolutionary conservation of Asprosin's role in glucose metabolism. Through binding assays, we determined Ptprf as Asprosin's interacting receptor in zebrafish liver. Zebrafish possess two Ptprf paralogs (Ptprfa/b), both hepatically expressed and binding Asprosin with high affinity. Genetic ablation of ptprfa/b reduced basal glucose levels and eliminated Asprosin-induced hyperglycemia. Conversely, overexpression of soluble Ptprf ligand-binding domains neutralized Asprosin's glucogenic effects. These findings were validated in mammals: Asprosin binds PTPRF in mice and humans, and Ptprf knockout mice showed blunted response to Asprosin. Our results establish Ptprf as an evolutionarily conserved Asprosin receptor across vertebrates, providing mechanistic insights for developing therapies targeting this pathway for diabetes and obesity.

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ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Liver

SUBMITTER: Zhiquan Liu

LAB HEAD: Jianzhen Li

PROVIDER: PXD072402 | Pride | 2026-01-12

REPOSITORIES: Pride

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Project description:Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety about this. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a proteomic approach to identify specific SUMO targets responding to OGD and to investigate the potential these targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and glucose (ROG), confirming the high dynamism of this modification. Since OGD is highly related to brain ischemia we have also studied a cell line differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell protective effect largely depending on their sumoylation and that maintaining the sumoylation capacity of the coregulator NAB2 is also important to face OGD. Conversely, the sumoylation of the pluripotency factor OCT4, which is a target for the SUMO protease SENP7 after ROG, seems to block its cell survival-promoting capacity. Thus, better outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected factors.

			Action	DRS
	23091408_LZQ_2-minus.raw	Raw
	23091408_LZQ_2-plus.raw	Raw
	23101301_LZQ_1-Plus.raw	Raw
	23101301_LZQ_1-minus.raw	Raw
	23101301_LZQ_3-Plus.raw	Raw

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Ptprf is the conserved receptor for Asprosin’s glucogenic effects in vertebrates

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