title: Aristolochia manshuriensis Kom inhibits adipocyte differentiation by regulation of ERK1/2 and Akt pathway.
abstract: Aristolochia manshuriensis Kom (AMK) is a traditional medicinal herb used for the treatment of arthritis, rheumatism, hepatitis, and anti-obesity. Because of nephrotoxicity and carcinogenicity of AMK, there are no pharmacological reports on anti-obesity potential of AMK. Here, we showed AMK has an inhibitory effect on adipocyte differentiation of 3T3-L1 cells along with significantly decrease in the lipid accumulation by downregulating several adipocyte-specific transcription factors including peroxisome proliferation-activity receptor γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBP-α) and C/EBP-β, which are critical for adipogenesis in vitro. AMK also markedly activated the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway including Ras, Raf1, and mitogen-activated protein kinase kinase 1 (MEK1), and significantly suppressed Akt pathway by inhibition of phosphoinositide-dependent kinase 1 (PDK1). Aristolochic acid (AA) and ethyl acetate (EtOAc) fraction of AMK with AA were significantly inhibited TG accumulation, and regulated two pathway (ERK1/2 and Akt) during adipocyte differentiation, and was not due to its cytotoxicity. These two pathways were upstream of PPAR-γ and C/EBPα in the adipogenesis. In addition, gene expressions of secreting factors such as fatty acid synthase (FAS), adiponectin, lipopreotein lipase (LPL), and aP2 were significantly inhibited by treatment of AMK during adipogenesis. We used the high-fat diet (HFD)-induced obesity mouse model to determine the inhibitory effects of AMK on obesity. Oral administration of AMK (62.5 mg/kg/day) significantly decreased the fat tissue weight, total cholesterol (TC), and low density lipoprotein-cholesterol (LDL-C) concentration in the blood. The results of this study suggested that AMK inhibited lipid accumulation by the down-regulation of the major transcription factors of the adipogensis pathway including PPAR-γ and C/EBP-α through regulation of Akt pathway and ERK 1/2 pathway in 3T3-L1 adipocytes and HFD-induced obesity mice, and AA may be main act in inhibitory effects of AMK during adipocyte differentiation.
authors.affiliation: Traditional Korean Medicines (TKM)-Based Herbal Drug Research, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kwak
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Lee
authors.forename: Taesoo
authors.initials: T
authors.lastname: Kim
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Ahn
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Cho
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.forename: Youn-Hwan
authors.initials: YH
authors.lastname: Hwang
authors.forename: Jin Yeul
authors.initials: JY
authors.lastname: Ma
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D030022:Aristolochia / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D010936:Plant Extracts; D012333:RNA, Messenger; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3