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Inhibitory effects of Rocaglamide-A on PPARγ-driven adipogenesis through regulation of mitotic clonal expansion involving the JAK2/STAT3 pathway

Authors
Ha, Yoon-suKim, Taek-KyongPark, Ki-SunHwang, SeonghwanKim, JeongkyuKim, Seung-Jin
Issue Date
Jun-2022
Publisher
Elsevier B.V.
Keywords
Adipogenesis; Cell cycle; JAK2/STAT3; PPARγ; Rocaglamide-A
Citation
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, v.1867, no.6
Journal Title
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume
1867
Number
6
URI
https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/61322
DOI
10.1016/j.bbalip.2022.159148
ISSN
1388-1981
1879-2618
Abstract
Inhibition of adipogenesis is an important strategy for obesity treatment. Rocaglamide-A (Roc-A) is a natural herbal medicine isolated from the genus Aglaia (family Meliaceae), which has a cyclopenta[b]benzofuran core structure. Roc-A exhibits various pharmacological effects against diverse human cancer cells. However, the exact role of Roc-A during adipogenesis in adipocytes has not been studied at all. In this study, we demonstrate that Roc-A is crucial for reducing adipogenesis via downregulating PPARγ transcriptional activity. Consistently, Western-blot and RT-PCR analyses clearly showed that Roc-A inhibits the expression of PPARγ target genes and lipogenic markers in a dose-dependent manner along with suppression of lipid accumulation, in both 3T3-L1 cells and mouse adipose-derived stem cells. Mechanistically, Roc-A significantly decreased STAT3 phosphorylation in a dose-dependent manner in 3T3-L1 adipocytes. In particular, we confirmed that Roc-A effectively suppressed the expression of genes involved in cell-cycle regulation, such as cyclin A, B, D1, and E1, early during mitotic clonal expansion in 3T3-L1 adipocytes, and this effect was abolished by the JAK2/STAT3 activator FGF2. Taken together, our results demonstrated that Roc-A reduces adipogenesis by inhibiting PPARγ transactivation and STAT3 phosphorylation and thus may serve as a therapeutic target in obesity. © 2022
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자연과학대학 (생명과학과)
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