Evaluation of the Effect of Co-administration of IRAK Inhibitor and Pioglitazone on PPAR-γ, GLUT-4, TNF-α, and Leptin Genes Expression in Adipose Tissue of Insulin-resistant Mice

Document Type : Original Article


1 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Department of Biochemistry, Biophysics, Genetics and Nutrition, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

3 Assistant Professor, Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

4 Assistant Professor, Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran



Background: The worldwide prevalence of diabetes is increasing. Diabetes is a complex disease that results from impaired secretion of insulin or insulin resistance. In adipose tissue, insulin increases glucose uptake by stimulating the transfer of glucose transporter type 4 (GLUT-4) to the plasma membrane. In this study, the effect of IRAK inhibitor (IRAKi) and pioglitazone on genes expression in adipose tissue of insulin resistant mice was evaluated.
Methods: Mice were randomly divided into 6 groups (n= 8 each), five groups of which were fed a high-fat diet and one group received a normal diet for 12 weeks. The treatment with pioglitazone and IRAKi was performed for 2 weeks. At the end of the study, the animals were sacrificed and the adipose tissue and blood samples were collected. The expression of GLUT4, TNF-α, peroxisome proliferator-activated receptor gamma (PPARγ), and Lepin were determined by real-time PCR in the adipose tissue. The malondialdehyde (MDA) level and total antioxidant capacity (TAC) in serum were measured. Results were analyzed by SPSS 22.
Results: The data showed that the combination of IRAKi and pioglitazone increased PPARγ expression, leptin and TAC levels in serum, and reduced TNF-α expression and MDA levels. The GLUT4 expression in adipose tissue was not significant between studied groups. Pioglitazone and IRAKi improved insulin function by inhibiting inflammation signaling.
Conclusion: According to the results of this study, IRAKi may be an appropriate target for inhibiting inflammation and related disorders, including insulin resistance.


Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103(2):137-49.
Esteves JV, Enguita FJ, Machado UF. MicroRNAs-Mediated regulation of skeletal muscle GLUT4 expression and translocation in insulin resistance. J Diabetes Res 2017; 2017:7267910.
Craik C. 基因的改变NIH Public Access. Bone. 2008;23(1):1–7.
Esteghamati A, Etemad K, Koohpayehzadeh J, Abbasi M, Meysamie A, Noshad S, et al. Trends in the prevalence of diabetes and impaired fasting glucose in association with obesity in Iran: 2005-2011. Diabetes Res Clin Pract 2014; 103(2):319-27.
De Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett 2008; 582(1):97-105.
Fang P, Yu M, Guo L, Bo P, Zhang Z, Shi M. Galanin and its receptors: a novel strategy for appetite control and obesity therapy. Peptides 2012; 36(2):331-9.
Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 2011; 18(2):139-43.
Xu P, Hong F, Wang J, Wang J, Zhao X, Wang S, et al. DBZ is a putative PPARγ agonist that prevents high fat diet-induced obesity, insulin resistance and gut dysbiosis. Biochim Biophys Acta Gen Subj 2017; 1861(11):2690-701.
Gillentine MA, Berry LN, Goin-Kochel RP, Ali MA, Ge J, Guffey D, et al. the cognitive and behavioral phenotypes of individuals with CHRNA7 duplications. J Autism Dev Disord 2017; 47(3):549-62.
Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, et al. Hepatic fatty acid transporter Cd36 Is a common target of LXR, PXR, and PPARγ in promoting steatosis. Gastroenterology 2008; 134(2):556-67.
Wang Z, Wesche H, Stevens T, Walker N, Yeh WC. IRAK-4 Inhibitors for Inflammation. Curr Top Med Chem 2009; 9(8):724-37.
Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol 2012; 821:1-14.
Yadav H, Jain S, Yadav M, Sinha PR, Prasad GB, Marotta F. Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats. Dig Liver Dis 2009; 41(7):500-8.
Li Z, Younger K, Gartenhaus R, Joseph AM, Hu F, Baer MR, et al. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. J Clin Invest 2015; 125(3):1081-97.
Vilela BS, Vasques AC, Cassani RS, Forti AC, Pareja JC, Tambascia MA, et al. The HOMA-adiponectin (HOMA-AD) Closely Mirrors the HOMA-IR Index in the screening of insulin resistance in the Brazilian metabolic syndrome study (BRAMS). PLoS One 2016; 11(8):e0158751.
Rogero MM, Calder PC. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients 2018; 10(4):432.
Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol Metab 2012; 23(5):205-15.
Kumari M, Wang X, Lantier L, Lyubetskaya A, Eguchi J, Kang S, et al. IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest 2016; 126(8):2839-54.
Kampmann U, Christensen B, Nielsen TS, Pedersen SB, Ørskov L, Lund S, et al. GLUT4 and UBC9 protein expression is reduced in muscle from type 2 diabetic patients with severe insulin resistance. PLoS One 2011; 6(11):e27854.
Al-Hilali HA, Abduljaleel AK. The role of TNF and Resistin Gene+ 299 (G/A) polymorphism in the development of insulin resistance in non-obese Type 2 Diabetes Mellitus Iraqi patients. Int J Curr Microbiol App Sci 2015; 4(10):475-86.
Xu H, Teoman Uysal K, David Becherer J, Arner P, Hotamisligil GS. Altered tumor necrosis factor-α (TNF-α) processing in adipocytes and increased expression of transmembrane TNF-α in obesity. Diabetes 2002; 51(6):1876-83.
Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates interleukin-6 and tumor necrosis factor-α gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 2004; 286(2):E234-8.
Ahmad R, Shihab PK, Thomas R, Alghanim M, Hasan A, Sindhu S, et al. Increased expression of the interleukin-1 receptor-associated kinase (IRAK)-1 is associated with adipose tissue inflammatory state in obesity. Diabetol Metab Syndr 2015; 7:71.
Maitra U, Singh N, Gan L, Ringwood L, Li L. IRAK-1 contributes to lipopolysaccharide-induced reactive oxygen species generation in macrophages by inducing NOX-1 transcription and Rac1 activation and suppressing the expression of antioxidative enzymes. J Biol Chem 2009; 284(51):35403-11.
Rajaie A, Allahyari M, Nazari-Robati M, Fallah H. Inhibition of interleukin-1 receptor-associated kinases 1/4, increases gene expression and serum level of adiponectin in mouse model of insulin resistance. Int J Mol Cell Med 2018; 7(3):185-92.
Verreth W, De Keyzer D, Pelat M, Verhamme P, Ganame J, Bielicki JK, et al. Weight loss-associated induction of peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice. Circulation 2004; 110(20):3259-69.
Jialal I, Adams-Huet B, Duong F, Smith G. Relationship between retinol-binding protein-4/adiponectin and leptin/adiponectin ratios with insulin resistance and inflammation. Metab Syndr Relat Disord 2014; 12(4):227-30.
Fernández-Riejos P, Najib S, Santos-Alvarez J, Martín-Romero C, Pérez-Pérez A, González-Yanes C, et al. Role of leptin in the activation of immune cells. Mediators Inflamm 2010; 2010:568343.
Rahimipanah M, Hamedi M, Mirzapour M. Antioxidant activity and phenolic contents of Persian walnut ( Juglans regia L .) green husk extract. African Journal of Food Science and Technology 2010; 1(4):105-11.
Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH, et al. Antioxidant status in patients with uncomplicated insulin‐dependent and non‐insulin‐dependent diabetes mellitus. Eur J Clin Invest 1997; 27(6):484-90.
Höhn A, König J, Grune T. Protein oxidation in aging and the removal of oxidized proteins. J Proteomics 2013; 92:132-59.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107(9):1058-70.
Athreya K, Xavier MF. Antioxidants in the treatment of cancer. Nutr Cancer 2017; 69(8):1099-104.