Susanti Vina Yanti, Sasaki Tsutomu, Yokota-Hashimoto Hiromi, Matsui Sho, Lee Yong-Soo, Kikuchi Osamu, Shimpuku Mayumi, Kim Hye-Jin, Kobayashi Masaki, Kitamura Tadahiro
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
Obesity (Silver Spring). 2014 Oct;22(10):2115-9. doi: 10.1002/oby.20838. Epub 2014 Jul 14.
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.
下丘脑是控制能量平衡的脑中枢。下丘脑弓状核中的厌食性阿黑皮素原（POMC）神经元和促食欲的AgRP神经元在能量平衡调节中起关键作用。FoxO1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⁺）依赖性脱乙酰酶Sirt1去乙酰化。POMC神经元中胰岛素抵抗性组成型核FoxO1（CN-FoxO1）的过表达会导致肥胖，而POMC神经元中Sirt1的过表达会导致消瘦。在此测试了POMC神经元中Sirt1的过表达是否能挽救由胰岛素抵抗性CN-FoxO1引起的肥胖。
分析POMC神经元特异性CN-FoxO1/Sirt1双敲入（DKI）小鼠。
在雄性DKI小鼠中挽救了CN-FoxO1敲入小鼠的肥胖表型。雄性DKI小鼠中恢复了CN-FoxO1小鼠中观察到的氧气消耗减少、肥胖增加和POMC神经元减少的情况，且不影响食物摄入量和运动活性。在小鼠胚胎成纤维细胞和下丘脑N41细胞中，Sirt1的过表达降低了FoxO1的乙酰化和蛋白质水平，但不影响其核定位。
Sirt1通过去乙酰化降低FoxO1蛋白水平，挽救了雄性小鼠POMC神经元中由胰岛素抵抗性CN-FoxO1诱导的肥胖。Sirt1改善了由中枢胰岛素抵抗遗传模型引起的肥胖。
