AUTOPHAGY 2016, VOL. 12, NO. 4, 709–710 http://dx.doi.org/10.1080/15548627.2016.1151597
AUTOPHAGIC PUNCTUM
Emerging role of mammalian autophagy in ketogenesis to overcome starvation Ayano Takagi, Shinji Kume, Hiroshi Maegawa, and Takashi Uzu Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga, Japan
ABSTRACT
ARTICLE HISTORY
Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissuespecific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.
Received 27 January 2016 Revised 30 January 2016 Accepted 3 February 2016
Starvation is a life-threatening event for all organisms, and tightly regulated mechanisms have evolved to overcome this challenge. Autophagy is an evolutionarily conserved intracellular catabolic process that is activated under starvation conditions. Less complex organisms with deficient autophagic processes die during starvation, highlighting the importance of autophagy for survival. Autophagy is also activated in mammalian tissues experiencing prolonged starvation. However, the physiological role of starvation-induced autophagy in mammals has not been fully elucidated. Glucose, fatty acids, and ketone bodies are energy sources for living mammalian cells. Of these, glucose and ketone bodies can be utilized for ATP production in the brain. Therefore, gluconeogenesis from amino acid metabolites and ketogenesis from fatty acids are critical for maintaining brain energy homeostasis and physiological activity during starvation in mammals. The liver is a critical regulator of both gluconeogenesis and ketogenesis. Additionally, skeletal muscle and the kidneys also support gluconeogenesis and ketogenesis during starvation. Starvation promotes autophagy in all of these organs, raising the hypothesis that autophagy may regulate starvation-induced gluconeogenesis and/or ketogenesis in mammals. To reveal this hypothesis, we have recently examined the effect of autophagy deficiency on starvation-induced
KEYWORDS
autophagy; ketogenesis; kidney; lipid droplet; liver; starvation
gluconeogenesis and ketogenesis in mice lacking Atg5 (autophagy-related 5) in specific tissues including the liver, skeletal muscle, and kidney proximal tubular cells. Deficient autophagy does not alter glucose homeostasis during starvation, regardless of tissues. Additionally, neither skeletal muscle-specific nor kidney-specific autophagy deficiency affects ketogenesis. However, liver-specific autophagy deficiency partially but significantly attenuates starvationinduced ketogenesis. These findings indicate that autophagy is involved in hepatic ketogenesis during starvation. Hepatic autophagic activity is completely inhibited in liverspecific Atg5-deficient mice, whereas ketogenesis is partially impaired. This finding suggests that ketogenesis in other organs may compensate for the impaired ketogenesis in liver-specific autophagy-deficient mice. Therefore, we evaluated glucose and ketone metabolism during starvation in liver- and skeletal muscle-specific Atg5 double tissue knockout mice and liver- and kidney-specific Atg5 double tissue knockout mice to address this question. Similar to results from single tissue-specific autophagy-deficient mice, glucose metabolism during starvation is unaffected in either of the double knockout mice. However, mice lacking autophagy in both the liver and kidneys— but not in both the liver and skeletal muscle—show even lower blood ketone levels and physical activity during starvation than mice with deficient autophagic activity in the liver alone. These
CONTACT Shinji Kume [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kaup. Punctum to: Takagi A, Kume S, Kondo M, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Haneda M, Chano T, et al. Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation. Sci Rep 2016; 6:18944; http://dx.doi.org/10.1038/srep18944. © 2016 Taylor & Francis
710
A. TAKAGI ET AL.
Figure 1. Role of autophagy in hepatic and renal ketogenesis during starvation. Ketogenesis is essential for maintenance of energy homeostasis in the brain during starvation. Starvation stimulates free fatty acid (FFA) release from adipopse tissues. These FFAs are taken up by the liver and kidney, with intracellular lipid droplets forming. Lipids are then oxidized within mitochondria to generate ketone bodies. Autophagy regulates lipid droplet formation in the liver and kidney during starvation.
results indicate that the kidneys, but not skeletal muscle, can compensate for impaired hepatic ketogenesis.
HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2) is a rate limiting enzyme in ketogenesis. We found that HMGCS2 expression levels in the liver and kidney significantly increase with prolonged starvation, but this change is not altered by autophagy deficiency. Since ketone bodies are generated from fatty acids, cells regulating ketogenesis must receive a sufficient supply of fatty acids from adipose tissues. These fatty acids must then undergo intracellular lipid droplet formation and oxidation. Of these processes, we found that autophagy deficiency markedly disturbs starvation-induced lipid droplet formation in the liver and also in the proximal tubular cells of the kidney. Our findings reveal that autophagy regulates starvationinduced ketogenesis in adult mammals. Additionally, Kuma et al. previously demonstrated reduced amino acid concentrations in plasma and tissues from systemic Atg5-deficient neonatal mice, suggesting that amino acid depletion may underlie neonatal death in these mice. Therefore, autophagy may be essential for maintaining homeostasis during starvation in both neonatal and adult mice. However, the mechanisms by which starvation-induced autophagy promotes survival may differ between neonatal or adult mice. Nevertheless, autophagy is essential for survival during starvation across species. Furthermore, we demonstrate that the kidney proximal tubular cells can produce ketone bodies during starvation. Whereas renal glucose metabolism has been well described, there have been few studies examining renal ketogenesis since it was first reported in the 1960s. Our results also serve as a reminder of the importance of the kidney as a metabolic organ to overcome starvation. Our study demonstrates that starvation-induced activation of autophagy and subsequent lipid droplet formation in the liver and kidney are essential for ketogenesis to maintain energy homeostasis and physical activity during starvation (Fig. 1). These results shed new light on the physiology of mammalian autophagy and starvation.
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
AUTOPHAGIC PUNCTUM
Emerging role of mammalian autophagy in ketogenesis to overcome starvation Ayano Takagi, Shinji Kume, Hiroshi Maegawa, and Takashi Uzu Department of Medicine, Shiga University of Medical Science, Tsukinowa-Cho, Seta, Otsu, Shiga, Japan
ABSTRACT
ARTICLE HISTORY
Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissuespecific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.
Received 27 January 2016 Revised 30 January 2016 Accepted 3 February 2016
Starvation is a life-threatening event for all organisms, and tightly regulated mechanisms have evolved to overcome this challenge. Autophagy is an evolutionarily conserved intracellular catabolic process that is activated under starvation conditions. Less complex organisms with deficient autophagic processes die during starvation, highlighting the importance of autophagy for survival. Autophagy is also activated in mammalian tissues experiencing prolonged starvation. However, the physiological role of starvation-induced autophagy in mammals has not been fully elucidated. Glucose, fatty acids, and ketone bodies are energy sources for living mammalian cells. Of these, glucose and ketone bodies can be utilized for ATP production in the brain. Therefore, gluconeogenesis from amino acid metabolites and ketogenesis from fatty acids are critical for maintaining brain energy homeostasis and physiological activity during starvation in mammals. The liver is a critical regulator of both gluconeogenesis and ketogenesis. Additionally, skeletal muscle and the kidneys also support gluconeogenesis and ketogenesis during starvation. Starvation promotes autophagy in all of these organs, raising the hypothesis that autophagy may regulate starvation-induced gluconeogenesis and/or ketogenesis in mammals. To reveal this hypothesis, we have recently examined the effect of autophagy deficiency on starvation-induced
KEYWORDS
autophagy; ketogenesis; kidney; lipid droplet; liver; starvation
gluconeogenesis and ketogenesis in mice lacking Atg5 (autophagy-related 5) in specific tissues including the liver, skeletal muscle, and kidney proximal tubular cells. Deficient autophagy does not alter glucose homeostasis during starvation, regardless of tissues. Additionally, neither skeletal muscle-specific nor kidney-specific autophagy deficiency affects ketogenesis. However, liver-specific autophagy deficiency partially but significantly attenuates starvationinduced ketogenesis. These findings indicate that autophagy is involved in hepatic ketogenesis during starvation. Hepatic autophagic activity is completely inhibited in liverspecific Atg5-deficient mice, whereas ketogenesis is partially impaired. This finding suggests that ketogenesis in other organs may compensate for the impaired ketogenesis in liver-specific autophagy-deficient mice. Therefore, we evaluated glucose and ketone metabolism during starvation in liver- and skeletal muscle-specific Atg5 double tissue knockout mice and liver- and kidney-specific Atg5 double tissue knockout mice to address this question. Similar to results from single tissue-specific autophagy-deficient mice, glucose metabolism during starvation is unaffected in either of the double knockout mice. However, mice lacking autophagy in both the liver and kidneys— but not in both the liver and skeletal muscle—show even lower blood ketone levels and physical activity during starvation than mice with deficient autophagic activity in the liver alone. These
CONTACT Shinji Kume [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kaup. Punctum to: Takagi A, Kume S, Kondo M, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Haneda M, Chano T, et al. Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation. Sci Rep 2016; 6:18944; http://dx.doi.org/10.1038/srep18944. © 2016 Taylor & Francis
710
A. TAKAGI ET AL.
Figure 1. Role of autophagy in hepatic and renal ketogenesis during starvation. Ketogenesis is essential for maintenance of energy homeostasis in the brain during starvation. Starvation stimulates free fatty acid (FFA) release from adipopse tissues. These FFAs are taken up by the liver and kidney, with intracellular lipid droplets forming. Lipids are then oxidized within mitochondria to generate ketone bodies. Autophagy regulates lipid droplet formation in the liver and kidney during starvation.
results indicate that the kidneys, but not skeletal muscle, can compensate for impaired hepatic ketogenesis.
HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2) is a rate limiting enzyme in ketogenesis. We found that HMGCS2 expression levels in the liver and kidney significantly increase with prolonged starvation, but this change is not altered by autophagy deficiency. Since ketone bodies are generated from fatty acids, cells regulating ketogenesis must receive a sufficient supply of fatty acids from adipose tissues. These fatty acids must then undergo intracellular lipid droplet formation and oxidation. Of these processes, we found that autophagy deficiency markedly disturbs starvation-induced lipid droplet formation in the liver and also in the proximal tubular cells of the kidney. Our findings reveal that autophagy regulates starvationinduced ketogenesis in adult mammals. Additionally, Kuma et al. previously demonstrated reduced amino acid concentrations in plasma and tissues from systemic Atg5-deficient neonatal mice, suggesting that amino acid depletion may underlie neonatal death in these mice. Therefore, autophagy may be essential for maintaining homeostasis during starvation in both neonatal and adult mice. However, the mechanisms by which starvation-induced autophagy promotes survival may differ between neonatal or adult mice. Nevertheless, autophagy is essential for survival during starvation across species. Furthermore, we demonstrate that the kidney proximal tubular cells can produce ketone bodies during starvation. Whereas renal glucose metabolism has been well described, there have been few studies examining renal ketogenesis since it was first reported in the 1960s. Our results also serve as a reminder of the importance of the kidney as a metabolic organ to overcome starvation. Our study demonstrates that starvation-induced activation of autophagy and subsequent lipid droplet formation in the liver and kidney are essential for ketogenesis to maintain energy homeostasis and physical activity during starvation (Fig. 1). These results shed new light on the physiology of mammalian autophagy and starvation.
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
