Glucagon receptor signaling is not required for L-carbamoyl glutamate and L-citrulline induced ureagenesis in mice.

Glucagon regulates hepatic amino acid metabolism and increases ureagenesis. Ureagenesis is activated by N-acetylglutamate (NAG), formed via activation of N-acetylglutamate synthase (NAGS). Aiming to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we investigated whether glucagon receptor mediated activation of ureagenesis is required in a situation where NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle in vivo. Female C57Bl/6JRj mice, treated with a glucagon receptor antagonist (GRA), glucagon receptor knockout (Gcgr(-/-)) mice, and wild-type (Gcgr(+/+)) littermates received an intraperitoneal injection of N-carbamoyl glutamate (a stable variant of NAG) (Car), L-citrulline (Cit), Car and Cit (Car+Cit), or PBS. In separate experiments, Gcgr(-/-) and Gcgr(+/+) mice were administered N-carbamoyl glutamate and L-citrulline (wCar+wCit) in the drinking water for eight weeks. Car, Cit, and Car+Cit significantly (P 0.2), plasma amino acid (P>0.4) and urea concentrations (P>0.3), or the area of glucagon positive cells (P>0.3) in Gcgr(-/-) and Gcgr(+/+) mice. Our data suggest that glucagon mediated activation of ureagenesis is not required when NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle.