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.

Inhibitory Effects of Hwangryunhaedok-Tang in 3T3-L1 Adipogenesis by Regulation of Raf/MEK1/ERK1/2 Pathway and PDK1/Akt Phosphorylation

“…As shown in Figure 4(d), inhibitor of Erk phosphorylation (PD98059) treatment induced the significant inhibition of Erk phosphorylation, as a positive control for HRT treatment. Akt pathway has been shown to regulate adipocyte differentiation by modulation of PPAR- γ expression [14]. In this study, we found that HRT significantly decreased phosphorylation of Akt compared with control (Figure 5(a)).…”

Differential Protein Expression in White Adipose Tissue from Obesity-Prone and Obesity-Resistant Mice in Response to High Fat Diet and Anti-Obesity Herbal Medicines

“…Medicinal plants and their extracts have been verified as beneficial and are the oldest and most widespread form of medication to prevent diet-induced obesity [12,13,14]. Multiple natural products containing numerous bioactive compounds may result in synergistic activity that increases their bioavailability and action on multiple molecular targets.…”

Corni Fructus Containing Formulation Attenuates Weight Gain in Mice with Diet-Induced Obesity and Regulates Adipogenesis through AMPK

“…During adipogenesis of 3T3-L1 cells, peroxisome proliferator-activated receptor- γ (PPAR- γ ) and CCAAT/enhancer-binding protein- α (C/EBP- α ) play key roles as major transcription factors [5]. Expression of PPAR- γ , a transcription factor of the nuclear-receptor superfamily, and C/EBP- α , a member of the C/EBP family of basic-leucine zipper class of transcription factors, increased during differentiation of 3T3-L1 cells [6]. …”