"Cell Metabolism": Ptprd was first discovered to be a specific receptor of the appetite-stimulating hormone Asprosin in the central nervous system

Asprosin is a hormone caused by hunger
.

Early research by Atul Chopra's team found that Asprosin acts on the liver, and then activates the G protein-cAMP-PKA signaling pathway to promote the release of glucose into the blood from the liver, which plays a crucial role in the regulation of glucose metabolism in the body (Romere C, et al.
al.
Cell.
2016.
PMID: 27087445)
.

Subsequently, Atul Chopra's team collaborated with Xu Yong's team at Baylor College of Medicine to further discover that Asprosin can cross the blood-brain barrier, activate AgRP neurons in the hypothalamus that can promote appetite, and reduce appetite-suppressing pre-opioid melanocytic corticosteroids ( POMC) neuronal activity, thereby promoting feeding (Duerrschmid C, et al.
Nat Med.
2017.
PMID: 29106398)
.

Asprosin in people with hyperglycemia and hyperinsulinemia is about twice as high as that in normal people, so it has been proposed to use specific antibodies to neutralize Asprosin to treat obesity and insulin resistance
.

Atul Chopra's team has found that neutralizing antibodies specific to Asprosin can not only reduce blood sugar levels, but also reduce appetite and body weight (Ila Mishra, et al.
Elife.
2021.
PMID: 33904407)
.

However, it is still not fully understood how Asprosin activates the appetite-promoting AgRP neurons in the hypothalamus, thereby promoting eating
.

Recently, Atul Chopra's team once again made a breakthrough in Asprosin-related research, and the related results were published in the famous journal Cell Metabolism (Mishra I, et al.
Cell Metab.
2022.
PMID: 35298903)
.

Screenshot of the front page of the paper.
Previous studies have reported that Olfr734 is the receptor of Asprosin in the liver (Li E, et al.
Cell Metab.
2019.
PMID: 31230984), which mediates the role of Asprosin in blood sugar regulation
.

But Atul Chopra's team found that Olfr734 was not expressed in AgRP neurons that respond to Asprosin and mediate the appetite-regulating effect of Asprosin
.

In addition, Olfr734 knockout mice did not show abnormal appetite
.

Therefore, the researchers speculate that there may be other receptors or signaling pathways that mediate the effects of Asprosin in the central nervous system
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In order to confirm this conjecture, the authors used a high-affinity specific antibody to Asprosin to obtain the protein that specifically binds to Asprosin in mouse brain tissue homogenate by co-immunoprecipitation
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Among the 58 binding proteins, only Protein Tyrosine Phosphatase Receptor δ (Ptprd) was a membrane receptor by protein profiling
.

Ptprd is a transmembrane receptor belonging to leukocyte common antigen-related protein class IIa and is abundantly expressed in the brain
.

Further, the authors found that Ptprd is highly expressed in AgRP neurons
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Ptprd is highly expressed in AgRP neurons and then, through three different analysis methods [Microscale thermophoresis (MST), Biolayer interferometry (BLI), Surface plasmon resonance (SPR)], the authors found that asprosin can bind to the extracellular domain of Ptprd
.

Further studies found that the systemic Ptprd knockout mice were much lower in food and body weight than control wild-type mice, along with lower energy expenditure
.

The authors then found that Ptprd was not expressed in the liver, and Ptprd-deficient mice did not have significant differences in blood glucose levels and functions of glucose metabolism compared with wild-type mice, suggesting that Ptprd does not mediate the peripheral regulation of blood glucose by Asprosin
.

Considering that it has been found in previous studies that Asprosin can directly activate AgRP neurons, thereby increasing the feeding of mice, the authors speculate that Ptprd may mediate the effect of Asprosin on AgRP neurons
.

As a result, they found that specific knockout of Ptprd in AgRP neurons could block the activation of Asprosin on AgRP neurons, and mice with specific knockout of Ptprd in AgRP neurons were well resistant to high-fat food.
caused weight gain
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Not only that, soluble small fragments of the ligand-binding domain of Ptprd can significantly reduce the level of Asprosin in mice, inhibit the activation of Asprosin on AgRP, and reduce the food and body weight gain of the mice
.

In summary, this study found for the first time that Ptprd is a specific receptor of the appetite-stimulating hormone Asprosin in the central nervous system, providing a new theoretical basis for the treatment of metabolic diseases (such as anorexia, obesity, etc.
).
potential drug targets
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The work was done by the Atul Chopra research team at Case Western Reserve University
.

The research team of Yong Xu at Baylor College of Medicine and Dr.
Yanlin He at the University of Louisiana (a postdoctoral fellow in the group of Prof.
Yong Xu and now an assistant professor at the Pennington Institute for Biological Studies at the University of Louisiana) provided important assistance
.

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