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 journalArticlepeer-review

73 Citations (Scopus)


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 languageEnglish
Pages (from-to)191-202
Number of pages12
JournalCell Metabolism
Issue number2
Publication statusPublished - 2009 Feb 4




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