Liver autophagy contributes to the maintenance of blood glucose and amino acid levels

Abstract

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.

Autophagy at the crossroads of catabolism and anabolism

“…Similar results were observed in primary mouse haematopoietic stem cells following metabolic stress due to cytokine withdrawal in vitro or nutrient starvation in vivo 54 . In addition, recent studies using liver-specific Atg7-null mice demonstrated that hepatic autophagy is critical for maintaining systemic blood glucose levels during fasting by converting autophagy-derived amino acids to glucose via hepatic gluconeogenesis 55 . Overall, these studies highlight the diverse functions of autophagy-derived amino acids in sustaining energy production via the TCA cycle and producing substrates that fuel gluconeogenesis.…”

Starvation Compromises Paneth Cells

“…22 Apart from its physiological function, autophagy can also be induced on starvation as an adaptive response that recycles macromolecules to provide nutrients and energy essential for survival. [11][12][13] Interestingly, Paneth cells of starved mice showed increased induction of autophagy. We hypothesize that the deviant granules in Paneth cells of starved mice may be caused by induction of autophagy on starvation in an attempt to maintain vital cellular functions at the expense of the physiological function of autophagy (namely, the regulation of Paneth cell granule development).…”

“…4 Enteral starvation and total parenteral nutrition, as applied to critically ill patients, are reported to result in increased gut wall permeability, a compromised immune system, and bacterial translocation. [5][6][7][8][9][10] Because autophagy, a process induced on starvation, [11][12][13] influences the generation of Paneth cell granules, 14 we hypothesize that enteral starvation impairs Paneth cell function, contributing to starvation-associated gut compromise.…”

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

“…14 We therefore examined the concentration of each of 20 amino acids in the liver of control and colchicine-treated fish. During the measured time period of starvation, the levels of some amino acids (including branched-chain amino acids) in the liver of control fish increased gradually and significantly (Fig.…”