Constitutively active glucagon receptor drives high blood glucose in birds

Abstract

As the body’s primary source of energy, the maintenance of blood glucose is indispensable for overall health and metabolic homeostasis. It is predominantly regulated by the glucagon receptor family which is highly conserved in vertebrates^1–4. Compared to other vertebrates, avian blood glucose levels are relatively high^5,6, yet its regulatory mechanisms have remained obscure for more than a century. We show that high hepatic expression of the avian glucagon receptor (GCGR) in association with constitutively active Gs signaling was dependent upon the interaction of different domains. In vivo experiments focusing on the regulation of constitutively active GCGR expression in hepatic cells led to correspondingly high blood glucose, rapid hepatic lipid utilization and high metabolic rates via downstream signaling pathway activation in fish, reptiles, birds, and mammals. Furthermore, we identified a point mutation in chicken at the proximal gene region that resulted in GCGR mRNA reduction and weight increase. Overexpressing a natural human GCGR mutation (hsGCGR^H339R) with modest constitutive activity in mice, demonstrated that high level expression of this variant augmented high blood glucose, while reducing body weight. The combination of high expression and constitutive activity of the glucagon receptor may have contributed to the evolution of flight in the ancestors of birds.