Abstract
Interferon regulatory factors (IRFs) are emerging as the metabolic transcriptional regulators in obesity/type-2 diabetes (T2D). IRF5 is implicated with macrophage polarization toward the inflammatory M1-phenotype, nonetheless, changes in the adipose expression of IRF5 in T2D and relationship of these changes with other markers of adipose inflammation remain unclear. Therefore, we determined the IRF5 gene expression in subcutaneous adipose tissue samples from 46 T2D patients including 35 obese (Body Mass Index/BMI 33.83 ± 0.42 kg/m2) and 11 lean/overweight individuals (BMI 27.55 ± 0.46 kg/m2) using real-time qRT-PCR. IRF5 protein expression was assessed using immunohistochemistry and confocal microscopy. Fasting plasma glucose, insulin, HbA1c, C-reactive protein, cholesterol, low- and high-density lipoproteins (LDL/HDL), and triglycerides were measured using commercial kits. IRF5 gene expression was compared with that of signature inflammatory markers and several clinico-metabolic indicators. The data (mean ± SEM) show the enhanced adipose IRF5 gene (p = 0.03) and protein (p = 0.05) expression in obese compared to lean/overweight diabetic patients. Adipose IRF5 transcripts in diabetic obese individuals associated positively with those of TNF-α, IL-18, IL-23A, CXCL8, CCL2, CCL7, CCR1/5, CD11c, CD68, CD86, TLR4/7/10, Dectin-1, FGL-2, MyD88, NF-κB, IRF3, and AML1 (p < 0.05). In diabetic lean/overweight subjects, IRF5 expression associated with BMI, body fat %age, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR, C-reactive protein (CRP), IL-5, and IL-1RL1 expression; while in all T2D patients, IRF5 expression correlated with that of IRF4, TLR2/8, and CD163. In conclusion, upregulated adipose tissue IRF5 expression in diabetic obese patients concurs with the inflammatory signatures and it may represent a potential marker for metabolic inflammation in obesity/T2D.
Highlights
In the pathogenesis of type-2 diabetes (T2D), obesity plays out as an independent risk factor of pivotal complications including insulin resistance and chronic low-grade inflammation called metabolic inflammation which is initiated by metabolic and inflammatory cells responding to overnutrition and a positive energy balance
We recently reported that increased adipose tissue IRF5 expression in non-diabetic obese individuals associated with body mass index (BMI), percent body fat (PBF), and potential markers of adipose inflammation [20]; subcutaneous adipose tissue IRF5 expression in the diabetic obese patients and the relationship between IRF5 expression and signatures of metabolic inflammation still remain unclear
The White adipose tissue (WAT) expansion in obesity has been linked to metabolic inflammation and with an increased risk of developing insulin resistance, metabolic syndrome and T2D
Summary
In the pathogenesis of type-2 diabetes (T2D), obesity plays out as an independent risk factor of pivotal complications including insulin resistance and chronic low-grade inflammation called metabolic inflammation which is initiated by metabolic and inflammatory cells responding to overnutrition and a positive energy balance. The exact triggers of obesity-associated metabolic inflammation remain unclear and may differ among tissues. Increasing evidence supports that metabolic inflammation is a consequence of obesity and it may play, in turn, a causative role in blunting insulin sensitivity and disrupting metabolic/energy homeostasis [1,2]. White adipose tissue (WAT) is known to store triglycerides from which lipids are mobilized to meet energy requirements as needed. WAT is subdivided into subcutaneous and visceral (abdominal/omental) depots with specific pathophysiological attributes and metabolic functions. Subcutaneous fat is the largest fat depot in humans which accounts for nearly 70–80%
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