Abstract
Elevated free fatty acid (FFA) is a key risk factor for insulin resistance (IR). Our previous studies found that mangiferin could decrease serum FFA levels in obese rats induced by a high-fat diet. Our research was to determine the effects and mechanism of mangiferin on improving IR by regulating FFA metabolism in HepG2 and C2C12 cells. The model was used to quantify PA-induced lipid accumulation in the two cell lines treated with various concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased insulin-stimulated glucose uptake, via phosphorylation of protein kinase B (P-AKT), glucose transporter 2 (GLUT2), and glucose transporter 4 (GLUT4) protein expressions, and markedly decreased glucose content, respectively, in HepG2 and C2C12 cells induced by PA. Mangiferin significantly increased FFA uptake and decreased intracellular FFA and triglyceride (TG) accumulations. The activity of the peroxisome proliferator-activated receptor α (PPARα) protein and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) and the fatty acid β-oxidation rate corresponding to FFA metabolism were also markedly increased by mangiferin in HepG2 and C2C12 cells. Furthermore, the effects were reversed by siRNA-mediated knockdown of PPARα. Mangiferin ameliorated IR by increasing the consumption of glucose and promoting the FFA oxidation via the PPARα pathway in HepG2 and C2C12 cells.
Highlights
Insulin resistance (IR) is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin [1]
MO, USA); 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for cytotoxicity was purchased from MP Biomedicals (CA, USA); 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]D-glucose (2-NBDG) for confocal microscopy experiments was obtained from Invitrogen Corporation (CA, USA); glucose transporter type 2 (GLUT2) and glucose transporter type 4 (GLUT4) were purchased from Abcam (Cambridge, UK); peroxisome proliferator-activated receptor α (PPARα), PPARα siRNA (h), antibody against fatty acid translocase (CD36), carnitine palmitoyltransferase 1 (CPT1), and Control + insulin
The PPARα protein (Figures 6(a) and 6(b)), glucose uptake (Figures 7(c) and 7(d)), P-AKT (Figures 7(e) and 7(f)), and glucose transporter 2 (GLUT2) and glucose transporter 4 (GLUT4) expressions (Figures 7(g) and 7(h)) were significantly attenuated, the glucose content was obviously increased (P < 0 05, Figures 7(i) and 7(j)), and the fatty acid β-oxidation rate was markedly decreased (Figures 8(a)– 8(b)), as well as the expressions of PPARα downstream proteins, including CPT1 and CD36, which were suppressed noticeably in the presence of PPARα siRNA in both HepG2 cells and C2C12 myotubes (P < 0 05, Figures 8(c)–8(f)). These results strongly suggest that mangiferin exerts its effect on ameliorating IR and promoting free fatty acid (FFA) uptake and oxidation via the PPARα signaling pathway in both HepG2 cells and C2C12 myotubes
Summary
Insulin resistance (IR) is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin [1]. The body produces insulin, but the cells in the body become resistant to it and are unable to use it as effectively, leading to high blood glucose [2]. Elevated plasma-free fatty acid (FFA) is a risk factor for IR and type 2 diabetes mellitus (T2DM) [3]. An excess of FFA in the blood causes increased accumulation of lipid metabolites in the liver and skeletal muscle and can further worsen IR, which is the core defect in T2DM. FFA and their metabolites can interfere with insulin signaling and inhibit insulin-stimulated glucose uptake and glycogen synthesis [4]. Lowering the blood FFA levels and reducing the lipid metabolite accumulations of peripheral tissues have been considered an effective strategy to improve IR and diabetes
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