Expression of TGR5 in adipose tissue in relation to metabolic impairment and adipose tissue dysfunction in human obesity

Abstract

Aim: Takeda G-protein-coupled receptor 5 (TGR5) is a functional receptor which mediates a variety of metabolic and immune processes and is involved in the regulation of adipocyte pathophysiology. Data on TGR5 in human adipose tissue are very limited. Therefore, the aims of this study were to investigate TGR5 expression in visceral adipose tissue (VAT) and explore its association with signs of VAT dysfunction and overt metabolic disease in individuals with obesity. Methods: Fifty obese candidates to bariatric surgery were recruited at Sapienza University, Rome, Italy. The expression of TGR5 and markers of VAT dysfunction were assessed by rt-PCR in omental fragments obtained intraoperatively. Page 2 of Barchetta et al. Metab Target Organ Damage 2021;1:8 https://dx.doi.org/10.20517/mtod.2021.04 12 Results: Individuals with higher VAT TGR5 levels (high-TGR5) had greater fasting glucose (P = 0.027) and worse lipid profile (total-cholesterol, P = 0.014; LDL-cholesterol, P = 0.022) than those with lower TGR5 (low-TGR5) expression. High-TGR5 subjects showed significantly higher expression of markers of AT-specific inflammation and insulin resistance, such as tissue metallopeptidase inhibitor 1 (TIMP1; P = 0.011), poly[ADP-ribose]polymerase 1 (PARP1, P = 0.034), and WNT1-inducible-signaling pathway protein 1 (WISP1, P = 0.05), apoptosis (caspase 7, P = 0.031), and lipid trafficking (ANGPTL4, P < 0.001), compared to low-TGR5 patients. High VAT TGR5 expression predicted the presence of abnormal glucose metabolism with AUROC = 0.925 (95%CI: 0.827-1.00, P = 0.001) for the age-, sex-, and waist circumference-adjusted ROC curve. Conclusion: Our data show that increased VAT TGR5 is associated with VAT dysfunction and impaired lipid trafficking and predicts the presence of metabolic disorders in human obesity, overall adding novel insights to the understanding of TGR5-mediated pathways in the clinical setting.