Loss of hepatic autophagy induces α‐cell proliferation through impaired glutamine‐dependent gluconeogenesis

Autophagy, the highly conserved process of protein and organelle degradation, is suppressed in the liver by obesity and metabolic dysfunction-associated fatty liver disease and associated with the development of insulin resistance. We generated adult liver-inducible ATG3 knockout mice (Atg3^iLKO) to characterize pathways linking hepatic autophagy with metabolic homeostasis. Genetic loss of hepatic autophagy leads to a reduction in 16-h fasted glucose levels, a decrease in endogenous glucose production rates, and an increase in serum amino acids across the fed and fasted states. These changes collectively reflect a loss of hepatic gluconeogenic enzyme activity and not a general inability to degrade amino acids in the liver. Increased circulating glutamine levels resulting from this are associated with an induction of α-cell hyperplasia, leading to constitutively elevated glucagon levels. However, the loss of hepatic gluconeogenesis renders these animals highly glucagon resistant. Collectively, our data demonstrate that loss of hepatic autophagy is sufficient to activate the hepatic α-islet cell axis, leading to hyperglucagonemia with impaired glucose production.