Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood–brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
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This work was supported in part by the Baylor College of Medicine Mouse Metabolism Core (funded by NIH grant P30 DK079638), the Protein and Monoclonal Antibody Production Core (funded by NIH grant P30 CA125123), and the Mouse Phenotyping Core (funded by NIH grant UM1HG006348). Mammalian asprosin was provided by the University of North Carolina at Chapel Hill Protein Expression and Purification Core (funded by NIH grant P30 CA016086). Support was also provided by American Heart Association postdoctoral fellowships 16POST29630010 (C.D.) and 16POST27260254 (C.W.), the American Diabetes Association (grants 1-17-PDF-138 (Y.H.) and 1-17-JDF-009 (K.J.P.)), the NIDDK (grants 1R01DK111631 (K.J.P.), DK075087 (M.J.K.), DK101379 (Y.X.), and 1K08DK102529 (A.R.C.)), the NLM (grant LM012806; Z.Z.), the NHGRI Baylor–Johns Hopkins Center for Mendelian Genomics (grant UM1 HG006542; V.R.S.), the R.P. Doherty, Jr. –Welch Chair in Science Q-0022 (D.D.M.), the Intramural Research Program of the NIH (M.J.K.), and the USDA–CRIS (3092-5-001-059; Y.X.). A.R.C. is also supported by the Chao Physician-scientist Award, the Caroline Wiess Law scholar award, and a departmental laboratory startup package.