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Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats.

ABSTRACT: To investigate the effects of mitofusin-2 (MFN2) on insulin sensitivity and its potential targets in the liver of rats fed with a high-fat diet (HFD).Rats were fed with a control or HFD for 4 or 8 wk, and were then infected with a control or an MFN2 expressing adenovirus once a week for 3 wk starting from the 9(th) wk. Blood glucose (BG), plasma insulin and insulin sensitivity of rats were determined at end of the 4(th) and 8(th) wk, and after treatment with different amounts of MFN2 expressing adenovirus (10(8), 10(9) or 10(10) vp/kg body weight). BG levels were measured by Accu-chek Active Meter. Plasma insulin levels were analyzed by using a Rat insulin enzyme-linked immunosorbent assay kit. Insulin resistance was evaluated by measuring the glucose infusion rate (GIR) using a hyperinsulinemic euglycemic clamp technique. The expression or phosphorylation levels of MFN2 and essential molecules in the insulin signaling pathway, such as insulin receptor (INSR), insulin receptor substrate 2 (IRS2), phosphoinositide-3-kinase (PI3K), protein kinase beta (AKT2) and glucose transporter type 2 (GLUT2) was assayed by quantitative real-time polymerase chain reaction and Western-blotting.After the end of 8 wk, the body weight of rats receiving the normal control diet (ND) and the HFD was not significantly different (P > 0.05). Compared with the ND group, GIR in the HFD group was significantly decreased (P < 0.01), while the levels of BG, triglycerides (TG), total cholesterol (TC) and insulin in the HFD group were significantly higher than those in the ND group (P < 0.05). Expression of MFN2 mRNA and protein in liver of rats was significantly down-regulated in the HFD group (P < 0.01) after 8 wk of HFD feeding. The expression of INSR, IRS2 and GLUT2 were down-regulated markedly (P < 0.01). Although there were no changes in PI3K-P85 and AKT2 expression, their phosphorylation levels were decreased significantly (P < 0.01). After intervention with MFN2 expressing adenovirus for 3 wk, the expression of MFN2 mRNA and protein levels were up-regulated (P < 0.01). There was no difference in body weight of rats between the groups. The levels of BG, TG, TC and insulin in rats were lower than those in the Ad group (P < 0.05), but GIR in rats infected with Ad-MFN2 was significantly increased (P < 0.01), compared with the Ad group. The expression of INSR, IRS2 and GLUT2 was increased, while phosphorylation levels of PI3K-P85 and AKT2 were increased (P < 0.01), compared with the Ad group.HFDs induce insulin resistance, and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.

SUBMITTER: Gan KX

PROVIDER: S-EPMC3602474 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats.

Gan Ke-Xin KX Wang Chao C Chen Jin-Hu JH Zhu Chun-Jing CJ Song Guang-Yao GY

World journal of gastroenterology 20130301 10

<h4>Aim</h4>To investigate the effects of mitofusin-2 (MFN2) on insulin sensitivity and its potential targets in the liver of rats fed with a high-fat diet (HFD).<h4>Methods</h4>Rats were fed with a control or HFD for 4 or 8 wk, and were then infected with a control or an MFN2 expressing adenovirus once a week for 3 wk starting from the 9(th) wk. Blood glucose (BG), plasma insulin and insulin sensitivity of rats were determined at end of the 4(th) and 8(th) wk, and after treatment with different ...[more]

PMID: 23538485

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Project description:BackgroundThe "multiple-hit" hypothesis is currently the most widely accepted theory for non-alcoholic fatty liver disease (NAFLD) pathogenesis. The present study aimed to investigate the effects of the water extract of artichoke (WEA) on NAFLD and its underlying mechanism.MethodsRats were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD and then treated with WEA at three doses (0.4, 0.8, and 1.6 g/kg body weight, BW) for 8 weeks. At the end of the intervention, serum biochemical parameters, hepatic antioxidant capacity, hepatic levels of pro-inflammatory cytokines, liver histopathology, hepatic inflammatory gene and lipid metabolism gene expression, and Akt and p-Akt (S473) protein levels were determined.ResultsThe body weight, liver weight, liver triglyceride (TG) and serum levels of TG, total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, glucose, and insulin were all significantly reduced in the WEA-treated groups (0.8 and 1.6 g/kg BW) compared with the HFD group (P < 0.01). A significant decrease in hepatic content of malondialdehyde (P < 0.01) and glutathione (P < 0.01), as well as a significant increase in liver superoxide dismutase activity (P < 0.01) were observed in WEA-treated groups (0.8 and 1.6 g/kg BW) compared to the HFD group. In addition, there was a marked decrease in the hepatic levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the WEA-treated groups compared to the HFD group (P < 0.01). In line with these findings, the histopathology of the livers of rats treated with WEA (0.8 and 1.6 g/kg BW) showed a decrease in steatosis, ballooning, and lobular inflammation. Mechanistically, the reduced hepatic TG content might be related to the downregulation of lipogenic genes (SREBP1c, FASN, SCD1) and upregulation of lipolytic gene (PPARα), and the improved insulin signaling might be associated with the observed increase in antioxidant activity and reduction in inflammation in the WEA-treated groups.ConclusionThe hepatoprotective role of WEA in NAFLD may be attributed to its anti-steatotic, antioxidant, anti-inflammatory, and anti-insulin resistance effects.

Project description:Sanye Tablet (SYT) is a patent prescription widely used in treating T2D and pre-diabetes, especially T2D comorbid with hypertriglyceridemia, for many years in China. However, the underlying mechanism that accounts for the anti-diabetic potential of SYT by regulating lipid-related intermediates remains to be elucidated. This study aimed to investigate the mechanism of SYT on lipid metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice by means of combining lipidomics and proteomics. The obese mice models were developed via HFD feeding for 20 consecutive weeks. Mice in the treatment group were given metformin and SYT respectively, and the effects of SYT on body weight, blood glucose, insulin sensitivity, fat accumulation in the organs, and pathological changes in the liver were monitored. Lipid metabolism was examined by lipidomics. Further determination of signaling pathways was detected by proteomics. The biological contributions of the compounds detected in SYT's chemical fingerprint were predicted by network pharmacology. SYT treatment reduced body weight, inhibited viscera and hepatic steatosis lipid accumulation, and prevented insulin resistance. Furthermore, it was found that circulatory inflammatory cytokines were reduced by SYT treatment. In addition, lipidomics analysis indicated that SYT targets lipid intermediates, including diacylglycerol (DAG) and Ceramide (Cer). Mechanistically, SYT positively affected these lipid intermediates by suppressing liver lipogenesis via downregulation of SREBP1/ACC and the JAK/STAT signaling pathway. Our results predicted that astragalin and rosmarinic acid might regulate the JAK-STAT pathway by targeting PIM2 and STAT1, respectively, while paeoniflorin and rosmarinic acid were likely to regulate inflammatory responses by targeting TNFα, IL-6, and IL-4 during T2D. Overall, our study provides supportive evidence for the mechanism of SYT's therapeutic effect on dysregulated lipid metabolism in diabesity.

Dataset Information

Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats.

Publications

Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats.

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