Abstract
Background: 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 NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action.Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMAIR and glucose infusion rate during euglycemic hyperinsulinemic clamp.Results: In both cohort 1 and cohort 2, NRG4 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 NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMAIR and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1.Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue.
Highlights
IntroductionThe modulation of brown adipose tissue activity and browning of white adipose tissue has been proposed as a promising therapeutic strategy in the treatment of obesity-associated metabolic disturbances (Wu et al, 2012; Bartelt and Heeren, 2014; Hepler et al, 2017; Rabhi et al, 2018; Zhang S. et al, 2018), with the intention of improving insulin sensitivity (Hepler et al, 2017; Rabhi et al, 2018) and hepatic steatosis (Huang et al, 2017), among others.Several studies pointed to neuregulins as an important family of ligands that regulate diverse aspects of glucose and lipid metabolism and energy balance
In cohort 1, VAT NRG4 gene expression was positively correlated with body mass index (BMI) and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes
Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and subcutaneous adipose tissue (SAT)
Summary
The modulation of brown adipose tissue activity and browning of white adipose tissue has been proposed as a promising therapeutic strategy in the treatment of obesity-associated metabolic disturbances (Wu et al, 2012; Bartelt and Heeren, 2014; Hepler et al, 2017; Rabhi et al, 2018; Zhang S. et al, 2018), with the intention of improving insulin sensitivity (Hepler et al, 2017; Rabhi et al, 2018) and hepatic steatosis (Huang et al, 2017), among others.Several studies pointed to neuregulins as an important family of ligands that regulate diverse aspects of glucose and lipid metabolism and energy balance. Nrg has been proposed as a marker of brown adipose tissue (BAT) activity in mice, being highly expressed in cold-induced BAT activity and white adipose tissue (WAT) browning (Rosell et al, 2014; Wang et al, 2014). In vitro experiments showed that brown adipocytes-derived NRG4 might promote the growth of neurites in adipose tissue, increasing sympathetic innervation, enhancing BAT activity and browning of WAT (Rosell et al, 2014). Wang et al (2014) reported that despite the abundant expression of Nrg in BAT, it seems dispensable for cold-induced hypothermia response, being Ucp and Dio induced to similar extent by cold exposure in WT and NRG4KO mice. We studied the possible association of NRG4 with insulin action
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