title: Wnt antagonist secreted frizzled-related protein 4 upregulates adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells.
abstract: With more than 1.4 billion overweight or obese adults worldwide, obesity and progression of the metabolic syndrome are major health and economic challenges. To address mechanisms of obesity, adipose tissue-derived mesenchymal stem cells (ADSCs) are being studied to detail the molecular mechanisms involved in adipogenic differentiation. Activation of the Wnt signalling pathway has inhibited adipogenesis from precursor cells. In our study, we examined this anti-adipogenic effect in further detail stimulating Wnt with lithium chloride (LiCl) and 6-bromo indirubin 3'oxime (BIO). We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic. Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation. Furthermore, there was significant 1.2-fold increase in peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα), and 1.3-fold increase in acetyl CoA carboxylase protein levels. In contrast, the expression of adipogenic proteins (PPARγ, C/EBPα, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments. These investigations demonstrate interplay between Wnt antagonism and Wnt activation during adipogenesis and indicate pathways for therapeutic intervention to control this process.
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Malini
authors.initials: M
authors.lastname: Visweswaran
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia; University of Lübeck, Lübeck, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Schiefer
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Arfuso
authors.affiliation: Ear Sciences Centre, University of Western Australia and Ear Science Institute Australia, Perth, Western Australia, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Dilley
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Arun
authors.initials: A
authors.lastname: Dharmarajan
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology*; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins