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

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. 14 C‐palmitate was used as tracer to track the fate of non‐esterified fatty acids or as substrate to measure β‐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‐α, 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. British Journal of Pharmacology (2008) 154 , 1016–1024; doi: 10.1038/bjp.2008.160 ; published online 12 May 2008