Inhibition of Interleukin-1 Receptor-Associated Kinases 1/4, Increases Gene Expression and Serum Level of Adiponectin in Mouse Model of Insulin Resistance

Abstract

Insulin resistance is a feature of most patients with type 2 diabetes mellitus. Epidemiological evidence suggest a correlation between inflammation and insulin resistant states such as obesity, but the underlying mechanisms are largely unknown. Interleukin-1 receptor-associated kinases (IRAK) play a central role in inflammatory responses by regulating the expression of various inflammatory genes in immune cells. This study was aimed to investigate the effect of IRAK inhibitor on gene transcription and serum concentration of adiponectin in insulin-resistant mice. Experimental mice were randomly divided into 6 groups: the healthy control group was fed a regular chow diet while other groups were fed with a high-fat diet for 12 weeks. After this period, the animals were treated with IRAK inhibitor, pioglitazone, both IRAK and pioglitazone, and DMSO, for two weeks. Adiponectin gene expression level was analyzed by real-time PCR. Additionally, serum adiponectin levels were measured by ELISA. Homeostasis model assessment-adiponectin (HOMA-AD) as an insulin sensitivity index was calculated. IRAK inhibitor and pioglitazone increased significantly the expression of adiponectin gene. Also, adiponectin concentration in the control group (9.67±1.1 μg/ml) increased to 25.34±2.04 μg/ml in pioglitazone treatment group. IRAK inhibitor also increased adiponectin concentration (18.24±1.53 μg/ml) but did not show a synergistic effect with pioglitazone when administered simultaneously (26.66±2.5 μg/ml). HOMA-AD was 0.33±0.04 in pioglitazone treated group, 0.6±0.13 in IRAK inhibitor group, and 0.31±0.03 in animals that received IRAKi and pioglitazone. Our findings suggest that increased adiponectin secretion from adipose tissue mediated by IRAK inhibitor may increase the insulin sensitivity in an animal model of insulin resistance.

Keywords: IRAK inhibitor; Insulin resistance; adiponectin; inflammation.

Fig. 1

Transcription level of adiponectin gene. Each IRAK inhibitor or pioglitazone increased the expression level of adiponectin gene in high-fat diet mice. IRAKi: IRAK inhibitor; pio: pioglitazone. *** P< 0.0001, ** P<0.01, * P<0.05 in comparison with control group

Fig. 2

Serum concentration of adiponectin. IRAK inhibitor or pioglitazone increased the serum concentration level of adiponectin in high- fat diet mice. IRAKi: IRAK inhibitor; pio: pioglitazone.*** P< 0.0001, ** P< 0.01, * P< 0.05 in comparison with control group

Fig. 3

Effects of IRAKi on HOMA-AD..IRAK inhibitor or pioglitazone decreased HOMA-AD in high-fat diet mice. IRAKi: IRAK inhibitor; pio: pioglitazone. *** P< 0.0001, ** P< 0.01, * P< 0.05 in comparison with control group

Fig. 4

Correlation between HOMA-IR and adiponectin. Correlation coefficient= -0.527; P< 0.0001