WISP2 regulates preadipocyte commitment and PPARγ activation by BMP4
WISP2 regulates preadipocyte commitment and PPARγ activation by BMP4
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DOI：
10.1073/pnas.1211255110
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发表时间：
2013-02-12
影响因子：
11.1
通讯作者：
Smith, Ulf
中科院分区：
文献类型：
--
作者：
Hammarstedt, Ann;Hedjazifar, Shahram;Smith, Ulf
体重增加后无法招募新的脂肪细胞导致与炎症和脂肪组织功能障碍相关的现有细胞的不适当扩大（肥大性肥胖）。我们发现，在人腹部皮下注射中，WNT 1诱导信号通路蛋白2（WISP 2）和其他WNT活化标志物的表达增加。以肥大性肥胖为特征的脂肪组织，伴有内脏脂肪积累增加和胰岛素抵抗。在s.c.脂肪组织，而不是内脏脂肪，确定了同样肥胖的个体的代谢综合征。WISP 2是一种新型脂肪因子，由脂肪前体细胞高度表达和分泌。敲低WISP 2诱导3 T3-L1和人前脂肪细胞的自发分化，并允许NIH 3 T3成纤维细胞通过骨形态发生蛋白4（BMP 4）定向于脂肪谱系。WISP 2与过氧化物酶体增殖物激活受体γ（PPAR γ）转录激活剂锌指蛋白423（Zfp 423）形成胞质复合物，并且该复合物以SMAD依赖性方式被BMP 4解离，从而允许Zfp 423进入细胞核，激活PPAR γ，并使细胞定向为脂肪谱系。通过表达缺乏内质网信号和分泌序列的突变Wisp 2蛋白，验证了细胞内Wisp 2蛋白对于BMP 4诱导的脂肪形成定型和PPAR γ激活的重要性。分泌的Wnt/Wisp 2也抑制分化和PPAR γ激活，尽管不是通过Zfp 423核转位。因此，成脂定型和分化受BMP 4和经典WNT信号传导之间的串扰调节，其中WISP 2起关键作用。此外，他们将WISP 2与肥厚性肥胖和代谢综合征联系起来。
Inability to recruit new adipose cells following weight gain leads to inappropriate enlargement of existing cells (hypertrophic obesity) associated with inflammation and a dysfunctional adipose tissue. We found increased expression of WNT1 inducible signaling pathway protein 2 (WISP2) and other markers of WNT activation in human abdominal s.c. adipose tissue characterized by hypertrophic obesity combined with increased visceral fat accumulation and insulin resistance. WISP2 activation in the s.c. adipose tissue, but not in visceral fat, identified the metabolic syndrome in equally obese individuals. WISP2 is a novel adipokine, highly expressed and secreted by adipose precursor cells. Knocking down WISP2 induced spontaneous differentiation of 3T3-L1 and human preadipocytes and allowed NIH 3T3 fibroblasts to become committed to the adipose lineage by bone morphogenetic protein 4 (BMP4). WISP2 forms a cytosolic complex with the peroxisome proliferator-activated receptor gamma (PPAR gamma) transcriptional activator zinc finger protein 423 (Zfp423), and this complex is dissociated by BMP4 in a SMAD-dependent manner, thereby allowing Zfp423 to enter the nucleus, activate PPAR gamma, and commit the cells to the adipose lineage. The importance of intracellular Wisp2 protein for BMP4-induced adipogenic commitment and PPAR gamma activation was verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPAR gamma activation, albeit not through Zfp423 nuclear translocation. Thus adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and canonical WNT signaling and where WISP2 plays a key role. Furthermore, they link WISP2 with hypertrophic obesity and the metabolic syndrome.