Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice.
Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice.
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DOI：
10.1016/j.cmet.2011.09.012
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发表时间：
2011-11-02
期刊：
影响因子：
29
通讯作者：
Accili D
中科院分区：
文献类型：
--
作者：
Banks AS;Kim-Muller JY;Mastracci TL;Kofler NM;Qiang L;Haeusler RA;Jurczak MJ;Laznik D;Heinrich G;Samuel VT;Shulman GI;Papaioannou VE;Accili D
fox01整合了多种代谢途径。营养水平调节fox01乙酰化，但这种翻译后修饰的功能后果尚不清楚。为了回答这个问题，我们培养了携带编码组成性乙酰化和乙酰化缺陷fox01蛋白的等位基因的小鼠。模仿组成型乙酰化的等位基因（Foxo1KQ/KQ）的纯合性导致胚胎致命性，这是由于心脏和血管生成缺陷。相比之下，组成性去乙酰化Foxo1等位基因（Foxo1KR/KR）纯合的小鼠表现出独特的代谢表型，即胰岛素对肝脏糖代谢的作用受损，但血浆脂质水平降低，呼吸商降低，与脂质使用优先状态一致。此外，Foxo1KR/KR小鼠在易感条件下（高脂肪饮食、糖尿病和胰岛素受体突变）表现出体重增加和胰岛素抵抗之间的分离，可能是由于脂肪组织中细胞因子产生减少。因此，在营养过剩时，乙酰化使FoxO1失活，而去乙酰化选择性地增强FoxO1活性，在营养缺乏时防止过度分解代谢。
FoxO1 integrates multiple metabolic pathways. Nutrient levels modulate FoxO1 acetylation, but the functional consequences of this posttranslational modification are unclear. To answer this question, we generated mice bearing alleles that encode constitutively acetylated and acetylation-defective FoxO1 proteins. Homozygosity for an allele mimicking constitutive acetylation (Foxo1KQ/KQ) results in embryonic lethality, due to cardiac and angiogenesis defects. In contrast, mice homozygous for a constitutively deacetylated Foxo1 allele (Foxo1KR/KR) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism, but decreased plasma lipid levels and low respiratory quotient, consistent with a state of preferential lipid usage. Moreover, Foxo1KR/KR mice show a dissociation between weight gain and insulin resistance in predisposing conditions (high fat diet, diabetes and Insulin receptor mutations), possibly due to decreased cytokine production in adipose tissue. Thus acetylation inactivates FoxO1 during nutrient excess whereas deacetylation selectively potentiates FoxO1 activity, protecting against excessive catabolism during nutrient deprivation.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
29
作者：
Banks AS;Kon N;Knight C;Matsumoto M;Gutiérrez-Juárez R;Rossetti L;Gu W;Accili D
通讯作者：
Accili D
影响因子：
15.9
作者：
Kido, Y;Burks, DJ;Accili, D
通讯作者：
Accili, D
影响因子：
29
作者：
Biddinger, Sudha B.;Hernandez-Ono, Antonio;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
15.9
作者：
Kitamura, Tadahiro;Kitamura, Yukari Ido;Accili, Domenico
通讯作者：
Accili, Domenico