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.
Highlights
Obesity is a major risk factor for a number of metabolic diseases including cardiovascular diseases, hypertension, and diabetes mellitus [1,2]
Experimental results demonstrate that extract of Aristolochia manshuriensis Kom (AMK) significantly inhibited 3T3-L1 preadipocytes differentiation in relation to the regulation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt pathway
Other studies showed that activation of Akt could induce the differentiation of 3T3-L1 adipocytes [19,31] and that Akt phosphorylation was inhibited in anti-adipogenesis [32,33]
Summary
Obesity is a major risk factor for a number of metabolic diseases including cardiovascular diseases, hypertension, and diabetes mellitus (type 2) [1,2]. Obesity is an increase in the number of differentiated mature adipocytes and a condition in which excess body fat has accumulated due to lipids becoming adipocytes [3,4,5]. In vitro model system for adipogensis is used the 3T3L1 cells which originally derived from mouse embryos [8]. In the process of adipogenesis, it is well-known that peroxisome proliferation-activity receptor-c (PPAR-c) and CCAAT/enhancer binding protein-a (C/EBP-a) are master regulators, [6,10] which leads to induce the expression of lipid metabolizing enzymes such as fatty acid binding protein (FABP) 4 and lipoprotein lipase (LPL) [7].
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