title: Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation.
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.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Takagi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakazawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.affiliation: Division of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada-machi, Kahoku-Gun, Ishikawa 920-0293, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Midorigaoka Higashinijyo, Asahikawa, Hokkaido 078-8510, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.affiliation: Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.affiliation: Institute of Medical Science and Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Frontier Research Labs, Institute for Innovation, Ajinomoto Co., Inc., Suzuki-cho, Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagao
authors.affiliation: Frontier Research Labs, Institute for Innovation, Ajinomoto Co., Inc., Suzuki-cho, Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000172:deficiency / Q000235:genetics; D001786:Blood Glucose; D005943:Gluconeogenesis; D007657:Ketone Bodies / Q000096:biosynthesis* / Q000097:blood; D007668:Kidney / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008322:Mammals; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D013217:Starvation / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D000071187:Autophagy-Related Protein 5; D001786:Blood Glucose; D007657:Ketone Bodies