The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors
The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors
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DOI：
10.1128/mcb.00685-09
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发表时间：
2010-02-01
影响因子：
5.3
通讯作者：
Ishii, Shunsuke
中科院分区：
文献类型：
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作者：
Maekawa, Toshio;Jin, Wanzhu;Ishii, Shunsuke
ATF-2 是转录因子 ATF/CREB 家族的成员，由应激激活蛋白激酶（例如 p38）激活。为了分析 ATF-2 家族转录因子的生理作用，我们培育了 Atf-2 和 Atf-2 相关基因 Cre-bpa 突变的小鼠。两个突变体的反式杂合子都很瘦并且白色脂肪组织（WAT）减少。 ATF-2 和 CRE-BPa 是骨形态发生蛋白 2 (BMP-2) 和 p38 依赖性诱导过氧化物酶体增殖物激活受体 γ 2 (PPAR γ 2)（介导脂肪细胞分化的关键转录因子）所必需的。由于储存的脂肪供应已被认为是抗肥胖治疗的可能目标，因此我们通过长期使用 p38 抑制剂治疗小鼠来测试 p38-ATF-2 通路的抑制是否会抑制脂肪细胞分化并导致 WAT 减少。在喂食 p38 抑制剂的小鼠中，高脂肪饮食 (HFD) 引起的肥胖显着减少。此外，p38 抑制剂还可减轻 HFD 诱导的胰岛素抵抗。在 p38 抑制剂治疗的小鼠中，WAT 中的巨噬细胞浸润减少，肿瘤坏死因子 α (TNF-α) 水平低于对照小鼠。因此，p38抑制剂可能提供一种新的抗肥胖治疗方法。
ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-alpha) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment.