Response to a long-term high-fat diet in the signature of genes involved in lipid metabolism in ApoE(-/-) mice.

High-fat diet (HFD)-induced lipid metabolism disorders are a critical feature of diet-induced insulin resistance (IR); however, the mechanisms underlying the tissue-specific effects of HFDs on the signature of genes involved in lipid metabolism have not been fully investigated. Glucose homeostasis and insulin sensitivity were monitored in chow-fed and HFD-fed ApoE mice using the hyperinsulinemic-euglycemic clamp technique. The signatures of genes involved in lipid metabolism were measured in the liver and adipose tissues by quantitative real-time polymerase chain reaction and Western blot analysis. Long-term HFD (for 16 weeks) resulted in marked abnormalities in glucose and lipid metabolism and induced IR in ApoE mice. Long-term HFD also markedly upregulated the messenger RNA (mRNA) expression of insulin-induced gene-2, sterol regulatory element-binding protein cleavage-activating protein and sterol regulatory element-binding protein-1 in the liver and/or adipose tissues, in parallel with an elevated insulin-induced gene-2 protein in the liver. However, HFD markedly downregulated the mRNA expression of sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and low-density lipoprotein receptor in the liver. Interestingly, long-term HFD markedly decreased adipose triglyceride lipase and peroxisome proliferator-activated receptor-γ mRNA, and adipose triglyceride lipase protein contents in the liver and/or adipose tissues. These findings provide a framework to understand the mechanisms by which long-term HFD regulates the gene signatures involved in lipid metabolism in the pathogenesis of diet-induced IR.