AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis.
AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis.
复制标题
DOI：
10.7554/elife.32656
复制
发表时间：
2018-02-13
期刊：
影响因子：
7.7
通讯作者：
Kemp BE
中科院分区：
文献类型：
--
作者：
Galic S;Loh K;Murray-Segal L;Steinberg GR;Andrews ZB;Kemp BE
AMP活化蛋白激酶（AMPK）是一种已知的全身能量稳态调节剂，但介导这些作用的下游AMPK底物并不完全清楚。AMPK通过磷酸化乙酰辅酶A羧化酶（ACC）1的Ser 79和ACC 2的Ser 212来抑制脂肪酸合成并促进脂肪酸氧化。使用具有Ser 79 Ala/Ser 212 Ala敲入突变（ACC DKI）的小鼠，我们发现ACC磷酸化的抑制导致响应于禁食或冷暴露的食欲降低。在亚热中性温度下，ACC DKI小鼠维持正常的能量消耗和产热，但不能增加食欲和减轻体重。我们证明，ACC DKI表型可以在野生型小鼠中使用生长素释放肽受体拮抗剂模仿，ACC DKI小鼠对生长素释放肽的食欲反应受损，表明ACC DKI小鼠具有生长素释放肽信号传导缺陷。这些数据表明，旨在抑制ACC磷酸化的治疗策略可能会抑制代谢应激后的食欲。
AMP-activated protein kinase (AMPK) is a known regulator of whole-body energy homeostasis, but the downstream AMPK substrates mediating these effects are not entirely clear. AMPK inhibits fatty acid synthesis and promotes fatty acid oxidation by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212. Using mice with Ser79Ala/Ser212Ala knock-in mutations (ACC DKI) we find that inhibition of ACC phosphorylation leads to reduced appetite in response to fasting or cold exposure. At sub-thermoneutral temperatures, ACC DKI mice maintain normal energy expenditure and thermogenesis, but fail to increase appetite and lose weight. We demonstrate that the ACC DKI phenotype can be mimicked in wild type mice using a ghrelin receptor antagonist and that ACC DKI mice have impaired orexigenic responses to ghrelin, indicating ACC DKI mice have a ghrelin signaling defect. These data suggest that therapeutic strategies aimed at inhibiting ACC phosphorylation may suppress appetite following metabolic stress.