Abstract
Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG-CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals.
Highlights
Because the liver is principally involved in gluconeogenesis and ketogenesis during starvation[7], we initially studied both processes in liver-specific autophagy-deficient mice
There was no significant difference between M-Atg5−/− and Atg5f/f mice in skeletal muscle ketone content after 36 h fasting (Fig. 1M). These results indicated that skeletal muscle autophagy was not contributing to the residual ketone levels in the starved L-Atg5−/− mice, though metabolic alteration of ketogenic amino acids might be involved in the mechanism compensating for impaired ketogenesis in L-Atg5−/− mice
The most important finding of this study is that autophagy is essential for starvation-induced lipid droplet formation and subsequent ketogenesis in adult mice
Summary
Western blots for Atg[5] and LC3II/LC3I proteins in liver tissues of mice fasted for 36 h. (J) Skeletal muscle-specific autophagy-deficient mice (M-Atg5−/−) were generated by crossbreeding Atg[5] f/f mice with Mlc-1f-Cre mice. Skeletal muscle provides glycogenic and ketogenic amino acids during starvation[11] and fatty acids released from adipose tissue play critical roles in gluconeogenesis and ketogenesis[12]. This study aimed to determine tissue-specific roles of autophagy in gluconeogenesis and ketogenesis during starvation in mice with autophagy deficiency in selected tissues
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