Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation

• Published in: Scientific reports 2016-01, Vol.6 (1), p.18944-18944, Article 18944
• Main Authors: Takagi, Ayano, Kume, Shinji, Kondo, Motoyuki, Nakazawa, Jun, Chin-Kanasaki, Masami, Araki, Hisazumi, Araki, Shin-ichi, Koya, Daisuke, Haneda, Masakazu, Chano, Tokuhiro, Matsusaka, Taiji, Nagao, Kenji, Adachi, Yusuke, Chan, Lawrence, Maegawa, Hiroshi, Uzu, Takashi
• Format: Article
• Language: English
• Subjects: 14; 14/19; 631/443/272; 631/443/319; 64; 64/60; 82; 82/29; Adipose tissue; Amino Acids - metabolism; Animals; Autophagy; Autophagy-Related Protein 5 - deficiency; Autophagy-Related Protein 5 - genetics; Blood; Blood Glucose; Energy balance; Gluconeogenesis; Homeostasis; Humanities and Social Sciences; Ketogenesis; Ketone Bodies - biosynthesis; Ketone Bodies - blood; Ketones; Kidney - metabolism; Kidneys; Lipid Metabolism; Liver; Liver - metabolism; Mammals; Mice; Mice, Knockout; multidisciplinary; Muscle, Skeletal - metabolism; Musculoskeletal system; Phagocytosis; Physical activity; Rodents; Science; Skeletal muscle; Starvation - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep18944

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.