title: Mechanisms of resveratrol-induced inhibition of clonal expansion and terminal adipogenic differentiation in 3T3-L1 preadipocytes.
abstract: We show that resveratrol prevents clonal expansion and terminal adipogenesis in 3T3-L1 preadipocytes. An early resveratrol effect was the inhibition of AKT and mitogen-activated protein kinase signaling, accompanied by down regulation of cyclin D1 expression, abrogation of retinoblastoma protein hyperphosphorylation, and subsequent inhibition of cell cycle reentry and clonal expansion, as indicated by cyclin A2 repression. Resveratrol inhibited terminal adipogenesis at the level of peroxisome proliferator-activated receptor-γ2 expression and activity. This was independent from the preceding inhibition of clonal expansion. Peroxisome proliferator-activated receptor-γ2 overexpression and activation partially restored fatty acid-binding protein 4 induction in resveratrol-treated 3T3-L1. Resveratrol activated AMP-activated protein kinase (AMPK) but did not induce PPAR-γ co-activator 1α (PGC1α) and mitochondrial biogenesis in 3T3-L1. Treatment with the Sirt1 inhibitor splitomicin augmented downregulation of peroxisome proliferator-activated receptor-γ2 and fatty acid-binding protein 4 expressions in resveratrol-treated 3T3-L1 and did not prevent the inhibition of terminal adipogenesis. Moreover, splitomicin could not obviate resveratrol-induced cyclin D1 repression, retinoblastoma protein hypophosphorylation, and inhibition of clonal expansion. Our data suggest that resveratrol inhibits clonal expansion and terminal adipogenesis in 3T3-L1 by several mechanisms.
authors.affiliation: Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, 6020 Innsbruck, Austria. werner.zwerschke@uibk.ac.at.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mitterberger
authors.forename: Werner
authors.initials: W
authors.lastname: Zwerschke
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D047495:PPAR gamma / Q000502:physiology; D011753:Pyrones / Q000494:pharmacology; D000077185:Resveratrol; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009281:Naphthalenes; D047495:PPAR gamma; D011753:Pyrones; D013267:Stilbenes; D045162:Thiazolidinediones; C444426:splitomicin; D048049:Extracellular Signal-Regulated MAP Kinases; D000077288:Troglitazone; D000077185:Resveratrol
keywords: 3T3-L1 preadipocytes; AKT; AMPK; Caloric restriction; Cyclin D1; MAPK; PGC1α; PPARγ2; Resveratrol; Retinoblastoma protein; Sirt1; cdki