Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome. Display omitted •Asprosin discovered as a fasting-induced glucogenic protein hormone•Asprosin induces hepatic glucose production by using cAMP as a second messenger•Asprosin is pathologically elevated with human and mouse insulin resistance•Reduction of asprosin protects against metabolic-syndrome-associated hyperinsulinism Circulating asprosin, a protein hormone, responds to low dietary glucose by triggering the release of liver glucose stores, and the reduction of asprosin protects against the hyperinsulinism associated with metabolic syndrome.