Constitutively active glucagon receptor drives high blood glucose in birds

The maintenance of blood glucose, the body's primary source of energy, is indispensable for overall health and metabolic homeostasis. It is regulated predominantly by the glucagon receptor family which is highly conserved in vertebrates^1-4. Compared with other vertebrates, avian blood glucose levels are relatively high^5,6, and blood glucose regulatory mechanisms in birds have remained unclear. Here we show that high hepatic expression of the avian glucagon receptor (GCGR) in association with constitutively active G_s signalling is dependent on the interaction of different domains. In vivo experiments showed that expression of constitutively active GCGR in hepatic cells led to correspondingly high blood glucose, rapid hepatic lipid utilization and high metabolic rates via downstream signalling pathway activation in fish, reptiles, birds and mammals. Furthermore, we identified a point mutation proximal to the GCGR gene region in chicken that resulted in reduced GCGR mRNA expression and increased body weight. Overexpressing a natural human GCGR variant (HsGCGR(H339R)) with modest constitutive activity in mice demonstrated that high expression of this variant increased blood glucose concentration and reduced body weight. In sum, we find that high expression and constitutive activity of GCGR may have contributed to the evolution of flight in the ancestors of birds.