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These adaptations are driven in part by glucagon, which promotes hepatic glucose production (HGP) and fatty acid oxidation (FAO) through mechanisms involving the transcription factor Foxo1. Autophagy is also activated during nutrient deprivation and maintains intracellular nutrient availability by recycling cellular components. However, whether autophagy supports glucagon\u2010Foxo1 signalling and the associated hepatic metabolic responses remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Hydroxychloroquine sulphate (HCQ) and AAV8\u2010shRNA\u2010\n                      <jats:italic>Atg7<\/jats:italic>\n                      were used to inhibit autophagy in control and liver\u2010specific Foxo1 knockout (L\u2010FKO) mice, and chloroquine (CQ) and siRNA\u2010\n                      <jats:italic>Atg7<\/jats:italic>\n                      were used to inhibit autophagy in mouse primary hepatocytes. Pyruvate and glucagon tolerance tests were performed in mice. HGP assays, gene expression analysis, western blotting and HPLC\u2010based amino acid measurements were conducted to evaluate glucose production, Foxo1 signalling, gluconeogenic and FAO\u2010related pathways and amino acid availability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that inhibition of autophagy reduced pyruvate\u2010stimulated glucose excursions in mice and glucose production in isolated primary hepatocytes, while showing a trend towards reducing glucagon\u2010stimulated glucose excursions in\u00a0vivo. It also attenuated glucagon\u2010responsive gluconeogenic and FAO\u2010related gene expression in primary hepatocytes. However, these effects of autophagy inhibition were markedly blunted in Foxo1\u2010deficient models. Mechanistically, suppression of autophagy significantly decreased Foxo1 protein abundance in association with impaired hepatic amino acid homeostasis, without corresponding changes in Foxo1 gene expression and not fully explained by proteasome\u2010dependent degradation. Importantly, supplementation with exogenous amino acids restored Foxo1 protein levels by 1.89\u2010fold under basal conditions and 1.35\u2010fold under glucagon\u2010treated conditions (\n                      <jats:italic>p\u2009&lt;<\/jats:italic>\n                      \u20090.05), and partially rescued HGP under autophagy\u2010inhibited conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify autophagy\u2010regulated amino acid homeostasis as a critical mechanism that sustains Foxo1 protein abundance and supports glucagon\u2010responsive hepatic metabolic adaptation during fasting.<\/jats:p>\n                  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