Sirt1 rescues the obesity induced by insulin-resistant constitutively-nuclear FoxO1 in POMC neurons of male mice.
Sirt1 rescues the obesity induced by insulin-resistant constitutively-nuclear FoxO1 in POMC neurons of male mice.
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DOI：
10.1002/oby.20838
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发表时间：
2014-10
期刊：
影响因子：
6.9
通讯作者：
Kitamura, Tadahiro
中科院分区：
文献类型：
--
作者：
Susanti, Vina Yanti;Sasaki, Tsutomu;Yokota-Hashimoto, Hiromi;Matsui, Sho;Lee, Yong-Soo;Kikuchi, Osamu;Shimpuku, Mayumi;Kim, Hye-Jin;Kobayashi, Masaki;Kitamura, Tadahiro
下丘脑是控制能量平衡的大脑中心。下丘脑弓状核中的厌氧性促黑素原皮质素（POMC）神经元和厌氧性AgRP神经元在能量平衡调节中起重要作用。fox01是一种受胰岛素信号调节的转录因子，可被烟酰胺腺嘌呤二核苷酸（NAD+-）依赖的去乙酰化酶Sirt1去乙酰化。POMC神经元中胰岛素抵抗组成核FoxO1 （CN-FoxO1）的过度表达导致肥胖，而POMC神经元中Sirt1的过度表达导致消瘦。我们测试了POMC神经元中Sirt1的过表达是否可以挽救胰岛素抵抗性CN-FoxO1引起的肥胖。对POMC神经元特异性CN-FoxO1/Sirt1双ki （DKI）小鼠进行分析。CN-FoxO1 KI小鼠的肥胖表型在雄性DKI小鼠中得以恢复。在CN-FoxO1小鼠中观察到的氧气消耗减少，脂肪增加和POMC神经元减少，在雄性DKI小鼠中获救，而不影响食物摄入和运动活动。Sirt1过表达降低小鼠胚胎成纤维细胞和下丘脑N41细胞中FoxO1乙酰化和蛋白水平，但不影响其核定位。Sirt1通过去乙酰化降低FoxO1蛋白，挽救了雄性小鼠POMC神经元中胰岛素抵抗性CN-FoxO1诱导的肥胖。Sirt1改善由中枢胰岛素抵抗遗传模型引起的肥胖。
The hypothalamus is the brain center that controls the energy balance. Anorexigenic proopiomelanocortin (POMC) neurons and orexigenic AgRP neurons in the arcuate nucleus of the hypothalamus plays critical roles in energy balance regulation. FoxO1 is a transcription factor regulated by insulin signaling that is deacetylated by Sirt1, a nicotinamide adenine dinucleotide- (NAD+-) dependent deacetylase. Overexpression of insulin-resistant constitutively-nuclear FoxO1 (CN-FoxO1) in POMC neurons leads to obesity, whereas Sirt1 overexpression in POMC neurons leads to leanness. Whether overexpression of Sirt1 in POMC neurons could rescue the obesity caused by insulin-resistant CN-FoxO1 was tested here. POMC neuron-specific CN-FoxO1/Sirt1 double-KI (DKI) mice were analyzed. The obese phenotype of CN-FoxO1 KI mice was rescued in male DKI mice. Reduced O2 consumption, increased adiposity, and fewer POMC neurons observed in CN-FoxO1 mice were rescued in male DKI mice without affecting food intake and locomotor activity. Sirt1 overexpression decreased FoxO1 acetylation and protein levels without affecting its nuclear localization in mouse embryonic fibroblasts and hypothalamic N41 cells. Sirt1 rescues the obesity induced by insulin-resistant CN-FoxO1 in POMC neurons of male mice by decreasing FoxO1 protein through deacetylation. Sirt1 ameliorates obesity caused by a genetic model of central insulin resistance.
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影响因子：
4.8
作者：
Qiang, Li;Banks, Alexander S.;Accili, Domenico
通讯作者：
Accili, Domenico
影响因子：
3.7
作者：
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通讯作者：
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影响因子：
8.2
作者：
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通讯作者：
Kitamura, Tadahiro
影响因子：
15.9
作者：
Kitamura, T;Nakae, J;Accili, D
通讯作者：
Accili, D
影响因子：
29
作者：
Rossi J;Balthasar N;Olson D;Scott M;Berglund E;Lee CE;Choi MJ;Lauzon D;Lowell BB;Elmquist JK
通讯作者：
Elmquist JK