Journal
AUTOPHAGY
Volume 7, Issue 7, Pages 727-736Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.7.7.15371
Keywords
amino acid; autophagy; liver; gluconeogenesis; insulin; phosphoenolpyruvate carboxykinase
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [16590253, 19390079, 14380308, 18076005]
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [16590253, 18076005, 22700656, 14380308, 21000012, 19390079, 21570155] Funding Source: KAKEN
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Both anabolism and catabolism of the amino acids released by starvation-induced autophagy are essential for cell survival, but their actual metabolic contributions in adult animals are poorly understood. Herein, we report that, in mice, liver autophagy makes a significant contribution to the maintenance of blood glucose by converting amino acids to glucose via gluconeogenesis. Under a synchronous fasting-initiation regimen, autophagy was induced concomitantly with a fall in plasma insulin in the presence of stable glucagon levels, resulting in a robust amino acid release. In liver-specific autophagy (Atg7)-deficient mice, no amino acid release occurred and blood glucose levels continued to decrease in contrast to those of wild-type mice. Administration of serine (30 mg/animal) exerted a comparable effect, raising the blood glucose levels in both control wild-type and mutant mice under starvation. Thus, the absence of the amino acids that were released by autophagic proteolysis is a major reason for a decrease in blood glucose. Autophagic amino acid release in control wild-type livers was significantly suppressed by the prior administration of glucose, which elicited a prompt increase in plasma insulin levels. This indicates that insulin plays a dominant role over glucagon in controlling liver autophagy. These results are the first to show that liver-specific autophagy plays a role in blood glucose regulation.
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