Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure
Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure
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DOI：
10.2337/db07-0698
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发表时间：
2008-03-01
期刊：
影响因子：
7.7
通讯作者：
Hayashi, Yoshitake
中科院分区：
文献类型：
--
作者：
Nakae, Jun;Cao, Yongheng;Hayashi, Yoshitake
目的 - 脂肪组织是各种生理途径、能量平衡和葡萄糖稳态的整合器。含叉头框蛋白O亚家族（FoxO）1在转录水平介导胰岛素作用。然而，FoxO1在脂肪组织中的生理作用仍不清楚。
研究设计与方法 - 在本研究中，我们利用脂肪细胞蛋白2（aP(2)）启动子/增强子和缺失羧基末端反式激活结构域的突变型FoxO1（FLAG Δ256），构建了脂肪组织特异性FoxO1转基因小鼠（aP(2)-FLAG - Δ256）。利用这些小鼠，我们分析了FLAG Δ256过表达对葡萄糖代谢和能量稳态的影响。
结果 - 在高脂饮食下，aP(2)-FLAG - Δ256小鼠表现出葡萄糖耐量和胰岛素敏感性改善，同时伴有脂肪细胞变小，白色脂肪组织（WAT）中脂联素（adipoq）和葡萄糖转运蛋白4（Glut 4，Slc2a4）增加，肿瘤坏死因子α（Tnf）和趋化因子（C - C基序）受体2（Ccr2）基因表达水平降低。此外，aP(2)-FLAG - Δ256小鼠耗氧量增加，同时棕色脂肪组织（BAT）中过氧化物酶体增殖物激活受体γ辅激活因子（PGC） - 1α蛋白以及解偶联蛋白（UCP） - 1（Ucp1）、UCP - 2（Ucp2）和β3 - 肾上腺素能受体（Adrb3）的表达增加。在源自SV40大T抗原转基因小鼠冬眠瘤的T37i细胞中过表达FLAG Δ256，可增加PGC - 1α蛋白和Ucp1的表达。此外，在T37i细胞中敲低内源性FoxO1可增加Pgc1α（Ppargc1a）、Pgc1β（Ppargc1b）、Ucp1和Adrb3基因表达。
结论 - 这些数据表明，FoxO1通过调节脂肪细胞大小和脂肪组织特异性基因表达，以应对热量摄入过多，从而调节白色脂肪组织和棕色脂肪组织中的能量稳态。
OBJECTIVE-Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box-containing protein O subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear.RESEARCH DESIGN AND METHODS-In the present study, we generated adipose tissue-specific FoxO1. transgenic mice (adipocyte protein 2 [aP(2)]-FLAG-Delta 256) using an aP(2) promoter/enhancer and a mutant FoxO1 (FLAG Delta 256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAG Delta 256 on glucose metabolism and energy homeostasis.RESULTS-The aP(2)-FLAG-Delta 256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smaller-sized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis factor alpha (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP(2)-FLAG-Delta 256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and beta 3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAG Delta 256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1 alpha protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1 alpha (Ppargc1a), Pgc1 beta (Ppargc1b), Ucp1, and Adrb3 gene expression.CONCLUSIONS-These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake.