title: Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes.
abstract: Bouchardatine (1), a naturally occurring β-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of 1 was investigated in 3T3-L1 adipocytes. Our study showed that 1 could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPβ, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that 1 persistently activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of 1 on adipogenesis and lipogenesis. Our data suggest that 1 can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders.
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Rao
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Yat-sen Sun University, Guangzhou 510006, PR China. Electronic address: ceshzs@mail.sysu.edu.cn.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D026121:Indole Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D026121:Indole Alkaloids; D047495:PPAR gamma; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C000607206:bouchardatine; D051743:CCAAT-Enhancer-Binding Protein-delta; D055372:AMP-Activated Protein Kinases
keywords: 3T3-L1 adipocytes; Adipogenesis/lipogenesis; Anti-obesity; Bouchardatine; Lipid lowering