TitlePiceatannol, natural polyphenolic stilbene, inhibits adipogenesis via modulation of mitotic clonal expansion and insulin receptor-dependent insulin signaling in early phase of differentiation.
Publication TypeJournal Article
Year of Publication2012
AuthorsKwon, JYeon, Seo, SGwon, Heo, Y-S, Yue, S, Cheng, J-X, Lee, KWon, Kim, K-H
JournalJ Biol Chem
Volume287
Issue14
Pagination11566-78
Date Published2012 Mar 30
ISSN1083-351X
Keywords3T3-L1 Cells, Adenosine Triphosphate, Adipocytes, Adipogenesis, Animals, Cell Division, Cell Survival, Gene Expression Regulation, Insulin, Mice, Models, Molecular, Phenols, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Conformation, Proto-Oncogene Proteins c-akt, Receptor, Insulin, Signal Transduction, Stilbenes, Time Factors, Transcription Factors
Abstract

Piceatannol, a natural stilbene, is an analog and a metabolite of resveratrol. Despite a well documented health benefit of resveratrol in intervention of the development of obesity, the role of piceatannol in the development of adipose tissue and related diseases is unknown. Here, we sought to determine the function of piceatannol in adipogenesis and elucidate the underlying mechanism. We show that piceatannol inhibits adipogenesis of 3T3-L1 preadipocytes in a dose-dependent manner at noncytotoxic concentrations. This anti-adipogenic property of piceatannol was largely limited to the early event of adipogenesis. In the early phase of adipogenesis, piceatannol-treated preadipocytes displayed a delayed cell cycle entry into G(2)/M phase at 24 h after initiation of adipogenesis. Furthermore, the piceatannol-suppressed mitotic clonal expansion was accompanied by reduced activation of the insulin-signaling pathway. Piceatannol dose-dependently inhibited differentiation mixture-induced phosphorylation of insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/Akt pathway in the early phase of adipogenesis. Moreover, we showed that piceatannol is an inhibitor of IR kinase activity and phosphatidylinositol 3-kinase (PI3K). Our kinetics study of IR further identified a K(m) value for ATP of 57.8 μm and a K(i) value for piceatannol of 28.9 μm. We also showed that piceatannol directly binds to IR and inhibits IR kinase activity in a mixed noncompetitive manner to ATP, through which piceatannol appears to inhibit adipogenesis. Taken together, our study reveals an anti-adipogenic function of piceatannol and highlights IR and its downstream insulin signaling as novel targets for piceatannol in the early phase of adipogenesis.

DOI10.1074/jbc.M111.259721
Alternate JournalJ. Biol. Chem.
PubMed ID22298784
PubMed Central IDPMC3322826