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Crocetin improves the insulin resistance induced by high-fat diet in rats.

ABSTRACT: BACKGROUND AND PURPOSE: The amelioration of insulin resistance by treatment with crocetin is closely related to the hypolipidaemic effect. The present study is designed to clarify the insulin-sensitizing mechanism of crocetin by elucidating the mechanism of regulation of lipid metabolism by crocetin. EXPERIMENTAL APPROACH: Rats given a high-fat diet were treated with crocetin for 6 weeks before hyperinsulinaemic-euglycaemic clamp. 14C-palmitate was used as tracer to track the fate of non-esterified fatty acids or as substrate to measure beta-oxidation rate. Triglyceride clearance in plasma and lipoprotein lipase activity in tissues were tested. Content of lipids in plasma and tissues was determined. Real-time PCR was used to assay the level of mRNA from genes involved in non-esterified fatty acid and triglyceride uptake and oxidation. KEY RESULTS: Crocetin prevented high-fat-diet induced insulin resistance (increased clamp glucose infusion rate), raised hepatic non-esterified fatty acid uptake and oxidation, accelerated triglyceride clearance in plasma, enhanced lipoprotein lipase activity in liver, and reduced the accumulation of detrimental lipids (DAG and long-chain acyl CoA) in liver and muscle. Genes involved in hepatic lipid metabolism which are regulated by peroxisome proliferator-activated receptor-alpha, were modulated to accelerate lipid uptake and oxidation. CONCLUSIONS AND IMPLICATIONS: Through regulating genes involved in lipid metabolism, crocetin accelerated hepatic uptake and oxidation of non-esterified fatty acid and triglyceride, and reduced lipid availability to muscle, thus decreasing lipid accumulation in muscle and liver, and consequently improving sensitivity to insulin.

SUBMITTER: Sheng L

PROVIDER: S-EPMC2451043 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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Project description:AimTo 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).MethodsRats 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.ResultsAfter 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.ConclusionHFDs induce insulin resistance, and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.

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Crocetin improves the insulin resistance induced by high-fat diet in rats.

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