title: Identification of KMU-3, a novel derivative of gallic acid, as an inhibitor of adipogenesis.
abstract: Differentiation of preadipocyte, also called adipogenesis, leads to the phenotype of mature adipocyte. Excessive adipogenesis, however, is largely linked to the development of obesity. Herein we investigated a library of 53 novel chemicals, generated from a number of polyphenolic natural compounds, on adipogenesis. Strikingly, among the chemicals tested, KMU-3, a derivative of gallic acid, strongly suppressed lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, KMU-3 inhibited expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and fatty acid synthase (FAS) during adipocyte differentiation. Moreover, KMU-3 reduced expressions of adipokines, including retinol binding protein-4 (RBP-4), leptin, and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. Of further note, KMU-3 rapidly blocked the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) during the early stage of adipogenesis. Importantly, pharmacological inhibition studies revealed that AG490, a JAK-2/STAT-3 inhibitor suppressed adipogenesis and STAT-3 phosphorylation, implying that early blockage of STAT-3 activity is crucial for the KMU-3-mediated anti-adipogenesis. These findings demonstrate firstly that KMU-3 inhibits adipogenesis by down-regulating STAT-3, PPAR-γ, C/EBP-α, and FAS. This work shows that KMU-3 is an inhibitor of adipogenesis and thus may have therapeutic potential against obesity.
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu, Daegu, Republic of Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Park
authors.affiliation: Department of Chemistry, College of Natural Sciences, Keimyung University, Dalseo-gu, Daegu, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemistry, College of Natural Sciences, Keimyung University, Dalseo-gu, Daegu, Republic of Korea.
authors.forename: Victor Sukbong
authors.initials: VS
authors.lastname: Hong
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Yuseong-gu, Daejeon, Republic of Korea; Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Microbiology, College of Medicine, Yeungnam University, Nam-gu, Daegu, Korea.
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu, Daegu, Republic of Korea.
authors.forename: Byeong-Churl
authors.initials: BC
authors.lastname: Jang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D020738:Leptin / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
chemical_list: D001549:Benzamides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D018946:Chemokine CCL5; C491899:Fas protein, mouse; D020738:Leptin; C000603651:N-(4-(tert-butyl)phenyl)-3,4,5-trihydroxybenzamide; D047495:PPAR gamma; D012333:RNA, Messenger; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D050796:STAT3 Transcription Factor; D019014:fas Receptor; D005707:Gallic Acid