Neuregulin 4 Is a Novel Marker of Beige Adipocyte Precursor Cells in Human Adipose Tissue

Abstract

<b>Background:</b> Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating <i>NRG4</i> mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of <i>NRG4</i> with insulin action. <b>Methods:</b> SAT and VAT <i>NRG4</i> and markers of brown/beige (<i>UCP1, UCP3, and TMEM26</i>)-related gene expression were analyzed in two independent cohorts (<i>n</i> = 331 and <i>n</i> = 59). Insulin resistance/sensitivity was measured using HOMA_IR and glucose infusion rate during euglycemic hyperinsulinemic clamp. <b>Results:</b> In both cohort 1 and cohort 2, <i>NRG4</i> and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT <i>NRG4</i> gene expression was positively correlated with BMI and expression of <i>UCP1, UCP3, TMEM26</i>, and negatively with adipogenic (<i>FASN, PPARG</i>, and <i>SLC2A4</i>)- and inflammatory (<i>IL6 and IL8</i>)-related genes. In SAT, <i>NRG4</i> gene expression was negatively correlated with HOMA_IR and positively with <i>UCP1</i> and <i>TMEM26</i> gene expression. Multiple linear regression analysis revealed that expression of <i>TMEM26</i> gene was the best predictor of <i>NRG4</i> gene expression in both VAT and SAT. Specifically, <i>NRG4</i> and <i>TMEM26</i> gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (<i>p</i> < 0.001). In cohort 2, the significant association between <i>NRG4</i> and <i>TMEM26</i> gene expression in both VAT and SAT was confirmed, and SAT <i>NRG4</i> gene expression also was positively correlated with insulin action and the expression of <i>UCP1</i>. <b>Conclusion:</b> Current findings suggest <i>NRG4</i> gene expression as a novel marker of beige adipocytes in human adipose tissue.