Sex-Specific Differences in Adipose IRF5 Expression and Its Association with Inflammation and Insulin Resistance in Obesity

Abstract

Interferon regulatory factor 5 (IRF5) plays a pivotal role in innate immune responses and macrophage polarization. Although its role in obesity-associated inflammation has been described, sex-specific differences in adipose IRF5 expression and its association with immune and metabolic markers remain poorly defined. To evaluate sex-specific associations between adipose tissue (AT) IRF5 expression and key inflammatory and metabolic markers in overweight and obese individuals. Subcutaneous AT samples from overweight/obese male and female subjects were analyzed for IRF5 expression using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Correlation and multiple linear regression analyses were performed to identify its associations with inflammatory gene expression and metabolic parameters including insulin, glucose, HOMA-IR, and adipokines. RF5 gene and protein levels were significantly elevated in the AT of overweight/obese females compared to males (p < 0.0001), with expression increasing progressively with BMI in females but not in males. Despite these sex-dependent expression levels, IRF5 demonstrated consistent, sex-independent positive correlations with several core immune and inflammatory markers, including CCR5, CD11c, CD16, CD163, FOXP3, RUNX1, and MyD88. However, distinct sex-specific patterns emerged: in males, IRF5 correlated positively with classical pro-inflammatory markers such as IL-2, IL-6, IL-8, TNF-α, and IRAK1; whereas in females, IRF5 was associated with a broader array of immune markers, including chemokines (CCL7, CXCL11), pattern recognition receptors (TLR2, TLR8, TLR9), and macrophage markers (CD68, CD86), along with anti-inflammatory mediators such as IL-10 and IRF4. Notably, IRF5 expression in overweight/obese males, but not females, was significantly associated with metabolic dysfunction, showing positive correlations with fasting blood glucose, HbA1c, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) levels. Multiple regression analyses revealed sex-specific predictors of IRF5 expression, with metabolic (HOMA-IR) and inflammatory (IRAK1, MyD88) markers emerging in males, while immune-related genes (RUNX1, CD68, CCL7, MyD88) predominated in females. These findings underscore a sex-divergent role of IRF5 in AT, with implications for differential regulation of immune-metabolic pathways in obesity and its complications.

Keywords: FBG; HOMA-IR; HbA1c; adipose tissue IRF5; inflammatory markers; obesity.

Figure 1

Sex-related differences in adipose tissue IRF5 expression and its association with obesity. (A) Quantitative analysis of IRF5 mRNA expression in adipose tissue from males and females reveals significantly higher expression in females compared to males (p < 0.0001), indicating sex-dependent differences in IRF5 transcript levels. (B) Protein expression analysis of IRF5 by immunofluorescence confirms increased levels in adipose tissue from females versus males, as shown by box-and-whisker plot quantification of fluorescent intensity. (C) Representative immunofluorescence images of adipose tissue sections stained for IRF5 (green), nuclei (DAPI, blue), and cell membranes (Phalloidin, red) in male (bottom row) and female (top row) samples. Increased nuclear and cytoplasmic IRF5 expression is evident in female adipocytes. Scale bar = 20 μm. (D,E) Analysis of IRF5 transcript levels across BMI categories. In males (D), IRF5 expression does not significantly differ among lean, overweight, and obese individuals. In females (E), IRF5 expression increases progressively with BMI, with significantly higher levels in overweight and obese women compared to lean women (p < 0.05), indicating a strong association between IRF5 and obesity in females. **** p ≤ 0.0001.

Figure 2

Sex-specific associations between adipose tissue IRF5 expression and metabolic markers. (A,B) In overweight/obese male participants, adipose tissue (AT) IRF5 transcript levels showed a significant positive correlation with (A) fasting blood glucose (FBG) (r = 0.546, p = 0.007) and (B) HbA1c levels (r = 0.510, p = 0.010). (C,D) In contrast, no significant correlations were observed between AT IRF5 transcript levels and (C) fasting blood glucose or (D) HbA1c in overweight/obese female participants. Each data point represents an individual subject. Blue indicates males and purple indicates females. Solid lines represent linear regression fit.