Asprosin is a centrally-acting orexigenic hormone

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here, we demonstrate that plasma asprosin crosses the blood-brain-barrier and directly activates orexigenic AgRP(+) neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic POMC(+) neurons in a GABA-dependent manner, resulting in appetite stimulation and a drive to accumulate adiposity and body weight. Genetic deficiency of asprosin in humans results in a syndrome characterized by low appetite and extreme leanness, which is phenocopied by mice carrying similar mutations, and one that can be fully rescued by asprosin expression. Further, we found that obese humans and mice display pathologically elevated circulating asprosin concentrations, and neutralization of plasma asprosin using a monoclonal antibody reduces appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, asprosin, in addition to performing a glucogenic function, is a centrally-acting orexigenic hormone, and one that represents a potential therapeutic target to treat both obesity and diabetes.