Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2563-8. doi: 10.1073/pnas.1211255110. Epub 2013 Jan 28.
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 γ (PPARγ) 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 PPARγ, and commit the cells to the adipose lineage. The importance of intracellular Wisp2 protein for BMP4-induced adipogenic commitment and PPARγ activation was verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPARγ 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.
体重增加后无法招募新的脂肪细胞会导致现有细胞（肥大性肥胖）不适当增大，伴发炎症和功能失调的脂肪组织。我们发现，在伴有内脏脂肪堆积增加和胰岛素抵抗的肥大性肥胖的人类腹部皮下脂肪组织中，WNT1 诱导信号通路蛋白 2（WISP2）和其他 WNT 激活标志物的表达增加。皮下脂肪组织中 WISP2 的激活（而不是内脏脂肪）可在同样肥胖的个体中识别出代谢综合征。WISP2 是一种新型脂肪因子，高度表达并由脂肪前体细胞分泌。WISP2 的敲低诱导 3T3-L1 和人前脂肪细胞的自发分化，并允许 NIH 3T3 成纤维细胞通过骨形态发生蛋白 4（BMP4）被诱导为脂肪谱系。WISP2 与过氧化物酶体增殖物激活受体 γ（PPARγ）转录激活锌指蛋白 423（Zfp423）形成细胞质复合物，该复合物通过 SMAD 依赖性方式与 BMP4 解离，从而允许 Zfp423 进入细胞核，激活 PPARγ，并使细胞被诱导为脂肪谱系。通过表达缺乏内质网信号和分泌序列的突变 Wisp2 蛋白，验证了细胞内 Wisp2 蛋白对 BMP4 诱导的脂肪生成和 PPARγ 激活的重要性。分泌的 Wnt/Wisp2 也抑制分化和 PPARγ 激活，尽管不是通过 Zfp423 核易位。因此，脂肪生成和分化受 BMP4 和经典 WNT 信号的串扰调节，其中 WISP2 发挥关键作用。此外，它们将 WISP2 与肥大性肥胖和代谢综合征联系起来。
