Fasting-induced hypothermia and reduced energy production in mice lacking acetyl-CoA synthetase 2.
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.
Sakakibara
Iori
I
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
Fujino
Takahiro
T
Ishii
Makoto
M
Tanaka
Toshiya
T
Shimosawa
Tatsuo
T
Miura
Shinji
S
Zhang
Wei
W
Tokutake
Yuka
Y
Yamamoto
Joji
J
Awano
Mutsumi
M
Iwasaki
Satoshi
S
Motoike
Toshiyuki
T
Okamura
Masashi
M
Inagaki
Takeshi
T
Kita
Kiyoshi
K
Ezaki
Osamu
O
Naito
Makoto
M
Kuwaki
Tomoyuki
T
Chohnan
Shigeru
S
Yamamoto
Tokuo T
TT
Hammer
Robert E
RE
Kodama
Tatsuhiko
T
Yanagisawa
Masashi
M
Sakai
Juro
J
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*
D000255:Adenosine Triphosphate; D000106:Acetate-CoA Ligase