Rotenoisin A is a novel anti-adipogenic compound

• Published in: Bioorganic & medicinal chemistry letters 2019-01, Vol.29 (1), p.89-96
• Main Authors: Cho, Hang-Hee, Park, Hyeon Soo, Jang, Sun-Hee, Won, Chungkil, Kim, Hong-Duck, Kim, Tae Hoon, Cho, Jae-Hyeon
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Acetyl-CoA Carboxylase - antagonists & inhibitors; Acetyl-CoA Carboxylase - metabolism; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis - drug effects; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Antiadipogenic effect; Dose-Response Relationship, Drug; Mice; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Rotenoisin A; Rotenone - analogs & derivatives; Rotenone - chemistry; Rotenone - pharmacology; Structure-Activity Relationship; Transcription factors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.11.008

[Display omitted] •We investigated the anti-obesity effect of rotenoisin A in 3T3-Ll adipocytes.•Rotenoisin A reduced the expression of C/EBPα and PPARγ in 3T3-L1 adipocytes.•Rotenoisin A increased AMPK and ACC phosphorylation in 3T3-L1 adipocytes.•Rotenoisin A inhibited adipocyte differentiation and adipogenesis in 3T3-L1 cells. The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPβ, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPα and PPARγ and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down-regulation of critical adipogenic transcription factors, including C/EBPβ, C/EBPα, and PPARγ, through activation of the AMPK signaling pathway by rotenoisin A.