Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2

Iori Sakakibara; Takahiro Fujino; Makoto Ishii; Toshiya Tanaka; Tatsuo Shimosawa; Shinji Miura; Wei Zhang; Yuka Tokutake; Joji Yamamoto; Mutsumi Awano; Satoshi Iwasaki; Toshiyuki Motoike; Masashi Okamura; Takeshi Inagaki; Kiyoshi Kita; Osamu Ezaki; Makoto Naito; Tomoyuki Kuwaki; Shigeru Chohnan; Tokuo T. Yamamoto; Robert E Hammer; Tatsuhiko Kodama; Masashi Yanagisawa; Juro Sakai

doi:10.1016/j.cmet.2008.12.008

Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2

Iori Sakakibara, Takahiro Fujino, Makoto Ishii, Toshiya Tanaka, Tatsuo Shimosawa, Shinji Miura, Wei Zhang, Yuka Tokutake, Joji Yamamoto, Mutsumi Awano, Satoshi Iwasaki, Toshiyuki Motoike, Masashi Okamura, Takeshi Inagaki, Kiyoshi Kita, Osamu Ezaki, Makoto Naito, Tomoyuki Kuwaki, Shigeru Chohnan, Tokuo T. YamamotoRobert E Hammer, Tatsuhiko Kodama, Masashi Yanagisawa, Juro Sakai

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Acetate is activated to acetyl-CoA by acetyl-CoA synthetase 2 (AceCS2), a mitochondrial enzyme. Here, we report that the activation of acetate by AceCS2 has a specific and unique role in thermogenesis during fasting. In the skeletal muscle of fasted AceCS2^-/- mice, ATP levels were reduced by 50% compared to AceCS2^+/+ mice. Fasted AceCS2^-/- mice were significantly hypothermic and had reduced exercise capacity. Furthermore, when fed a low-carbohydrate diet, 4-week-old weaned AceCS2^-/- mice also exhibited hypothermia accompanied by sustained hypoglycemia that led to a 50% mortality. Therefore, AceCS2 plays a significant role in acetate oxidation needed to generate ATP and heat. Furthermore, AceCS2^-/- mice exhibited increased oxygen consumption and reduced weight gain on a low-carbohydrate diet. Our findings demonstrate that activation of acetate by AceCS2 plays a pivotal role in thermogenesis, especially under low-glucose or ketogenic conditions, and is crucially required for survival.

Original language	English (US)
Pages (from-to)	191-202
Number of pages	12
Journal	Cell Metabolism
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2008.12.008
State	Published - Feb 4 2009

Keywords

HUMDISEASE

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2008.12.008

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Sakakibara, I., Fujino, T., Ishii, M., Tanaka, T., Shimosawa, T., Miura, S., Zhang, W., Tokutake, Y., Yamamoto, J., Awano, M., Iwasaki, S., Motoike, T., Okamura, M., Inagaki, T., Kita, K., Ezaki, O., Naito, M., Kuwaki, T., Chohnan, S., ... Sakai, J. (2009). Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2. Cell Metabolism, 9(2), 191-202. https://doi.org/10.1016/j.cmet.2008.12.008

Sakakibara, I, Fujino, T, Ishii, M, Tanaka, T, Shimosawa, T, Miura, S, Zhang, W, Tokutake, Y, Yamamoto, J, Awano, M, Iwasaki, S, Motoike, T, Okamura, M, Inagaki, T, Kita, K, Ezaki, O, Naito, M, Kuwaki, T, Chohnan, S, Yamamoto, TT, Hammer, RE, Kodama, T, Yanagisawa, M & Sakai, J 2009, 'Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2', Cell Metabolism, vol. 9, no. 2, pp. 191-202. https://doi.org/10.1016/j.cmet.2008.12.008

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title = "Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2",

abstract = "Acetate is activated to acetyl-CoA by acetyl-CoA synthetase 2 (AceCS2), a mitochondrial enzyme. Here, we report that the activation of acetate by AceCS2 has a specific and unique role in thermogenesis during fasting. In the skeletal muscle of fasted AceCS2-/- mice, ATP levels were reduced by 50% compared to AceCS2+/+ mice. Fasted AceCS2-/- mice were significantly hypothermic and had reduced exercise capacity. Furthermore, when fed a low-carbohydrate diet, 4-week-old weaned AceCS2-/- mice also exhibited hypothermia accompanied by sustained hypoglycemia that led to a 50% mortality. Therefore, AceCS2 plays a significant role in acetate oxidation needed to generate ATP and heat. Furthermore, AceCS2-/- mice exhibited increased oxygen consumption and reduced weight gain on a low-carbohydrate diet. Our findings demonstrate that activation of acetate by AceCS2 plays a pivotal role in thermogenesis, especially under low-glucose or ketogenic conditions, and is crucially required for survival.",

keywords = "HUMDISEASE",

author = "Iori Sakakibara and Takahiro Fujino and Makoto Ishii and Toshiya Tanaka and Tatsuo Shimosawa and Shinji Miura and Wei Zhang and Yuka Tokutake and Joji Yamamoto and Mutsumi Awano and Satoshi Iwasaki and Toshiyuki Motoike and Masashi Okamura and Takeshi Inagaki and Kiyoshi Kita and Osamu Ezaki and Makoto Naito and Tomoyuki Kuwaki and Shigeru Chohnan and Yamamoto, {Tokuo T.} and Hammer, {Robert E} and Tatsuhiko Kodama and Masashi Yanagisawa and Juro Sakai",

note = "Funding Information: We thank Dr. Rob Rawson for critical reading of the manuscript; Drs. Peter Edwards and Mitsuhiro Watanabe for helpful discussions; and Kaori Ikeda, Junko Kuno, Satomi Takahashi, Yuko Kai, and Mika Nomiyama for technical assistance. This work was supported through ERATO JST, NIBIO by the NFAT project of the NEDO and by the Special Coordination Fund for Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology. This work was also supported, in part, by Astellas Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, and the Ono Medical Foundation. M.Y. is an Investigator of the Howard Hughes Medical Institute. J.S. is an Investigator of Translational Systems Biology and Medicine Initiative (TSBMI). ",

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doi = "10.1016/j.cmet.2008.12.008",

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T1 - Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2

AU - Sakakibara, Iori

AU - Fujino, Takahiro

AU - Ishii, Makoto

AU - Tanaka, Toshiya

AU - Shimosawa, Tatsuo

AU - Miura, Shinji

AU - Zhang, Wei

AU - Tokutake, Yuka

AU - Yamamoto, Joji

AU - Awano, Mutsumi

AU - Iwasaki, Satoshi

AU - Motoike, Toshiyuki

AU - Okamura, Masashi

AU - Inagaki, Takeshi

AU - Kita, Kiyoshi

AU - Ezaki, Osamu

AU - Naito, Makoto

AU - Kuwaki, Tomoyuki

AU - Chohnan, Shigeru

AU - Yamamoto, Tokuo T.

AU - Hammer, Robert E

AU - Kodama, Tatsuhiko

AU - Yanagisawa, Masashi

AU - Sakai, Juro

N1 - Funding Information: We thank Dr. Rob Rawson for critical reading of the manuscript; Drs. Peter Edwards and Mitsuhiro Watanabe for helpful discussions; and Kaori Ikeda, Junko Kuno, Satomi Takahashi, Yuko Kai, and Mika Nomiyama for technical assistance. This work was supported through ERATO JST, NIBIO by the NFAT project of the NEDO and by the Special Coordination Fund for Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology. This work was also supported, in part, by Astellas Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, and the Ono Medical Foundation. M.Y. is an Investigator of the Howard Hughes Medical Institute. J.S. is an Investigator of Translational Systems Biology and Medicine Initiative (TSBMI).

PY - 2009/2/4

Y1 - 2009/2/4

N2 - Acetate is activated to acetyl-CoA by acetyl-CoA synthetase 2 (AceCS2), a mitochondrial enzyme. Here, we report that the activation of acetate by AceCS2 has a specific and unique role in thermogenesis during fasting. In the skeletal muscle of fasted AceCS2-/- mice, ATP levels were reduced by 50% compared to AceCS2+/+ mice. Fasted AceCS2-/- mice were significantly hypothermic and had reduced exercise capacity. Furthermore, when fed a low-carbohydrate diet, 4-week-old weaned AceCS2-/- mice also exhibited hypothermia accompanied by sustained hypoglycemia that led to a 50% mortality. Therefore, AceCS2 plays a significant role in acetate oxidation needed to generate ATP and heat. Furthermore, AceCS2-/- mice exhibited increased oxygen consumption and reduced weight gain on a low-carbohydrate diet. Our findings demonstrate that activation of acetate by AceCS2 plays a pivotal role in thermogenesis, especially under low-glucose or ketogenic conditions, and is crucially required for survival.

AB - Acetate is activated to acetyl-CoA by acetyl-CoA synthetase 2 (AceCS2), a mitochondrial enzyme. Here, we report that the activation of acetate by AceCS2 has a specific and unique role in thermogenesis during fasting. In the skeletal muscle of fasted AceCS2-/- mice, ATP levels were reduced by 50% compared to AceCS2+/+ mice. Fasted AceCS2-/- mice were significantly hypothermic and had reduced exercise capacity. Furthermore, when fed a low-carbohydrate diet, 4-week-old weaned AceCS2-/- mice also exhibited hypothermia accompanied by sustained hypoglycemia that led to a 50% mortality. Therefore, AceCS2 plays a significant role in acetate oxidation needed to generate ATP and heat. Furthermore, AceCS2-/- mice exhibited increased oxygen consumption and reduced weight gain on a low-carbohydrate diet. Our findings demonstrate that activation of acetate by AceCS2 plays a pivotal role in thermogenesis, especially under low-glucose or ketogenic conditions, and is crucially required for survival.

KW - HUMDISEASE

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SN - 1550-4131

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JF - Cell Metabolism

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ER -

Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2

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