Asprosin-Ptprd Signaling: A Novel Target for Hypertension and Obesity

Abstract: Hypertension is the leading risk factor for cardiovascular disease and all-cause mortality worldwide. Asprosin is a newly discovered metabolic protein hormone. So far two metabolic functions of asprosin have been thoroughly investigated. Asprosin traffics to the liver and activates the G- protein-cAMP-PKA pathway resulting in rapid glucose release into the circulation, and it crosses the blood-brain-barrier and activates the AgRP+ (Agouti related peptide expressing neurons) neurons for appetite stimulation and Purkinje neurons of the cerebellum for thirst stimulation. We have identified Ptprd (Protein Tyrosine Phosphatase type delta) as the neural receptor that asprosin engages for appetite and thirst stimulation. We have now found that asprosin also engages Ptprd for blood pressure (BP) modulation via a neural circuitry distinct from the circuitry it employs for appetite or thirst stimulation. Ptprd is highly expressed in the oxytocinergic neurons of the hypothalamus and mice with genetic loss of Ptprd from oxytocin neurons show low BP. Our preliminary data further shows that mice with oxytocin neuron specific Ptprd loss do not present with any other metabolic deficits, such as in appetite, water intake, energy expenditure, activity levels or respiratory exchange ratio, indicating asprosin specific modulation of BP independent of other metabolic effects. This preponderance of evidence positions asprosin-Ptprd signaling as a modulator of BP, independent of its effects on food accretion and water accretion – via distinct brain centers. This project will test the hypothesis that asprosin and its receptor Ptprd regulate BP via the oxytocin neurons, and that pharmacological inhibition of asprosin-Ptprd axis can serve as a viable therapeutic strategy against hypertension.