WISP2 regulates preadipocyte commitment and PPARγ activation by BMP4

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 7; pp. 2563 - 2568
• Main Authors: Hammarstedt, Ann, Hedjazifar, Shahram, Jenndahl, Lachmi, Gogg, Silvia, Grünberg, John, Gustafson, Birgit, Klimcakova, Eva, Stich, Vladimir, Langin, Dominique, Laakso, Markku, Smith, Ulf
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.02.2013; National Acad Sciences
• Subjects: 3T3 L1 cells; Adipocytes; adipokines; adipose tissue; Adipose Tissue - metabolism; Adipose tissues; Analysis of Variance; Animals; Biological Sciences; Bone Morphogenetic Protein 4 - metabolism; bone morphogenetic proteins; CCN Intercellular Signaling Proteins - genetics; CCN Intercellular Signaling Proteins - metabolism; Cell Differentiation - physiology; Diabetes; DNA-Binding Proteins - metabolism; endoplasmic reticulum; fibroblasts; Gene Knockdown Techniques; Humans; Immunoblotting; Immunoprecipitation; inflammation; insulin resistance; Lipid metabolism; Mesenchymal stem cells; Mesenchymal Stem Cells - physiology; metabolic syndrome; Mice; Microscopy, Fluorescence; mutants; NIH 3T3 Cells; Obesity; PPAR gamma - metabolism; Real-Time Polymerase Chain Reaction; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; secretion; signal transduction; Small interfering RNA; Statistics, Nonparametric; transactivators; Transcription Factors - metabolism; Type 2 diabetes mellitus; visceral fat; weight gain; zinc finger motif
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1211255110

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.