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

ABSTRACT

Glucagon regulates the hepatic amino acid metabolism and increases ureagenesis. Ureagenesis is activated by N-acetylglutamate (NAG), formed via activation of N-acetylglutamate synthase (NAGS). With the aim 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 (Car; a stable variant of NAG), 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 8 wk. Car, Cit, and Car + Cit significantly (P < 0.05) increased plasma urea concentrations, independently of pharmacological and genetic disruption of glucagon receptor signaling (P = 0.9). Car increased blood glucose concentrations equally in GRA- and vehicle-treated mice (P = 0.9), whereas the increase upon Car + Cit was impaired in GRA-treated mice (P = 0.008). Blood glucose concentrations remained unchanged in Gcgr-/- mice upon Car (P = 0.2) and Car + Cit (P = 0.9). Eight weeks administration of wCar + wCit did not change blood glucose (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.NEW & NOTEWORTHY Hepatic ureagenesis is essential in amino acid metabolism and is importantly regulated by glucagon, but the exact mechanism is unclear. With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we here show, contrary to our hypothesis, that glucagon receptor-mediated activation of ureagenesis is not required when N-acetylglutamate synthase activity and/or N-acetylglutamate levels are sufficient to activate the first step of the urea cycle in vivo.