Insulin resistance induced by a high-fat diet is associated with the induction of genes related to leukocyte activation in rat peripheral leukocytes

Aims: Insulin resistance caused by a high-fat diet induces type 2 diabetes and its complications. In this study. we investigated gene expression changes in peripheral leukocytes with insulin resistance by conducting microarray analyses in rats with high-fat diet-induced insulin resistance. Main methods: After assessing insulin resistance in rats by an oral glucose tolerance test, we performed microarray analyses using peripheral leukocytes from normal rats and insulin-resistant rats after fasting. Real-time RT-PCR analyses were performed for several upregulated genes in the microarray data after fasting and at 3 h after a single oral glucose load. Key findings: Feeding rats a high-fat diet for 77 days induced moderate insulin resistance. Microarray analysis showed that the high-fat diet enhances many genes related to leukocyte activation. These upregulated genes included genes related to host defense, and many genes related to G-protein-coupled receptor/tyrosine receptor signaling. Moreover, many genes, such as Anxa1, S100a8, Il22ra2, Gng10, Csf3r and Cd302, showed further upregulation of their expression after a single oral glucose load. Exposure to high glucose and/or tumor necrosis factor-a which is known to be a factor that induces insulin resistance, enhanced the mRNA levels of DUSP1, ANXA1, IL1B, S100A8, IL22RA2, S100A9 and IRF1 in human monocyte-like U937 cells. Significance: These results suggest that the expression of genes related to leukocyte activation in peripheral leukocytes is associated with the development of moderate insulin resistance. (C) 2010 Elsevier Inc. All rights reserved.