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Abstract
Autophagy is a highly inducible intracellular degradation process. It is generally induced by nutrient starvation and suppressed by food intake. Mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is considered to be the major regulator of autophagy, but the precise mechanism of in vivo regulation remains to be fully characterized. Here, we examined the autophagy-suppressive effect of glucose, insulin, and amino acids in the liver and muscle in mice starved for 1 day. Refeeding after starvation with a standard mouse chow rapidly suppressed autophagy in both tissues, and this suppression was inhibited by rapamycin administration almost completely in the liver and partially in muscle, confirming that mTORC1 is indeed a crucial regulator in vivo. As glucose administration showed no major suppressive effect on autophagy, we examined the role of insulin and amino acids using hyperinsulinemic-euglycemic clamp and intravenous amino acid infusion techniques. Insulin administration showed a clear effect on the mTORC1-autophagy pathway in muscle, but had only a very weak effect in the liver. By contrast, amino acids were able to regulate the mTORC1-autophagy pathway in the liver, but less effectively in muscle. These results suggest that autophagy is differentially regulated by insulin and amino acids in a tissue-dependent manner.
Highlights
The in vivo mechanism of autophagy regulation remains unclear
We found that glucose has no major role in autophagy regulation, and that the effect of insulin on the mTORC1-autophagy pathway is greater in muscle than in the liver, whereas amino acids regulate the mTORC1-autophagy pathway more effectively in the liver than in muscle
We have demonstrated that mTORC1 and autophagy are mainly regulated by amino acids in the liver in vivo, whereas they can be regulated by insulin in skeletal muscle
Summary
The in vivo mechanism of autophagy regulation remains unclear. Results: The effect of insulin on mTORC1-autophagy is greater in muscle than in the liver, whereas that of amino acids is greater in liver than in muscle. Amino acids were able to regulate the mTORC1-autophagy pathway in the liver, but less effectively in muscle. These results suggest that autophagy is differentially regulated by insulin and amino acids in a tissue-dependent manner. Starvation activates transcription factor EB (TFEB), an important gene for lysosomal biogenesis, which induces various autophagy-related factors at the transcriptional level [20] It is uncertain whether mTORC1 is a major regulator of autophagy under physiological conditions in vivo. We investigated the relative contribution of glucose, insulin, and amino acids to regulation of mTORC1 and autophagy in the liver and muscle in vivo. We found that glucose has no major role in autophagy regulation, and that the effect of insulin on the mTORC1-autophagy pathway is greater in muscle than in the liver, whereas amino acids regulate the mTORC1-autophagy pathway more effectively in the liver than in muscle
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