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.
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Iori
authors.initials: I
authors.lastname: Sakakibara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujino
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tokutake
authors.forename: Joji
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Awano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwasaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Motoike
authors.forename: Masashi
authors.initials: M
authors.lastname: Okamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chohnan
authors.forename: Tokuo T
authors.initials: TT
authors.lastname: Yamamoto
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005215:Fasting; D007003:Hypoglycemia / Q000209:etiology; D007036:Hypothermia, Induced; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption; D022722:Thermogenesis / Q000502:physiology*
chemical_list: D000255:Adenosine Triphosphate; D000106:Acetate-CoA Ligase