title: Methyl gallate, a potent antioxidant inhibits mouse and human adipocyte differentiation and oxidative stress in adipocytes through impairment of mitotic clonal expansion.
abstract: Methyl gallate (MG) is a derivative of gallic acid and a potent antioxidant. In this study, we confirmed that MG treatment effectively inhibits lipid accumulation, which occurred mostly in the early stages of adipogenesis. We also showed that shortly after adipogenic induction, MG facilitated a G0/G1 cell cycle arrest. Mechanistic studies revealed that MG treatment inhibited ERK1/2 phosphorylation, which is a key regulator of the G1- to S-phase transition. Furthermore, MG treatment prevented the adipogenic hormonal stimuli-induced inhibition of the cyclin-dependent kinase inhibitor p27Kip1. This led to inhibition of the transcription factor E2F1 by preventing the phosphorylation of, and thereby activation of its destruction partner RB. MG treatment also downregulated factors that are upstream of RB-E2F1 signaling such as Cdk2, Cyclin E, Cdk4, and Cyclin D1 where Cyclin D3 level was unaffected. We also found that MG treatment markedly decreased the expression and phosphorylation of C/EBPβ, by phosphorylating, and therefore inactivating, GSK3β, which is a prerequisite for its DNA binding capacity, and thereby mitotic clonal expansion (MCE). Ultimately, MG treatment downregulates key terminal adipogenic transcription factors including C/EBPα, PPARγ, aP2 (Fabp4), and adiponectin. Moreover, MG also protects adipocytes from oxidative stress by alleviating intracellular reactive oxygen species and activating Nrf2, HO-1, and PRDX3. Thus, this study provides a mechanistic insight into the anti-adipogenic actions of MG. © 2016 BioFactors, 42(6):716-726, 2016.
authors.affiliation: Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.|Institute of Tissue Engineering, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.
authors.forename: Naimur
authors.initials: N
authors.lastname: Rahman
authors.affiliation: Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.|Institute of Tissue Engineering, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.
authors.forename: Miso
authors.initials: M
authors.lastname: Jeon
authors.affiliation: Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.|Institute of Tissue Engineering, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam, 330-090, Korea.
authors.forename: Yong-Sik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D052438:Adipocytes, White / Q000187:drug effects / Q000502:physiology*; D050156:Adipogenesis; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D017382:Reactive Oxygen Species; C052082:methyl gallate; D005707:Gallic Acid
keywords: G0/G1 cell cycle arrest; adipogenesis; methyl gallate; mitotic clonal expansion; oxidative stress