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.

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.

Keywords

Takeda G-protein-coupled receptor 5 / visceral adipose tissue / lipid metabolism / type 2 diabetes / angiopoietin-like proteins / farnesoid-X receptor / obesity

References

[1] Gertzen CGW,Häussinger D.The many facets of bile acids in the physiology and pathophysiology of the human liver.Biol Chem2021;402:1047-62

[2] Guo C,Yu Y.The G-protein-coupled bile acid receptor gpbar1 (tgr5) inhibits gastric inflammation through antagonizing NF-κB signaling pathway.Front Pharmacol2015;6:287 PMCID:PMC4675858

[3] Pols TW,Nomura M,Schoonjans K.The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation.J Hepatol2011;54:126-372 PMCID:PMC3650458

[4] Thomas C,Noriega L.TGR5-mediated bile acid sensing controls glucose homeostasis.Cell Metab2009;10:167-77 PMCID:PMC2739652

[5] Jadhav K,Xu Y.Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.Mol Metab2018;9:131-40 PMCID:PMC5870099

[6] Wang XX,Luo Y.FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity.J Am Soc Nephrol2018;29:118-37 PMCID:PMC5748904

[7] Brønden A.Gluco-metabolic effects of pharmacotherapy-induced modulation of bile acid physiology.J Clin Endocrinol Metab2020;105:362-73

[8] Velazquez-Villegas LA,Lemos V.TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue.Nat Commun2018;9:245 PMCID:PMC5770450

[9] Watanabe M,Mataki C.Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.Nature2006;439:484-9

[10] Schmid A,Thomalla M,Schäffler A.Evidence of functional bile acid signaling pathways in adipocytes.Mol Cell Endocrinol2019;483:1-10

[11] Cimini FA,Ciccarelli G.Adipose tissue remodelling in obese subjects is a determinant of presence and severity of fatty liver disease.Diabetes Metab Res Rev2021;37:e3358

[12] Barchetta I,Del Ben M.Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with Type 2 diabetes.Clin Sci (Lond)2016;130:1753-62

[13] Barchetta I,Capoccia D.WISP1 is a marker of systemic and adipose tissue inflammation in dysmetabolic subjects with or without type 2 diabetes.J Endocr Soc2017;1:660-70 PMCID:PMC5686652

[14] Barchetta I,Ceccarelli V.Angiopoietin-like protein 4 overexpression in visceral adipose tissue from obese subjects with impaired glucose metabolism and relationship with lipoprotein lipase.Int J Mol Sci2020;21:7197 PMCID:PMC7582588

[15] Svensson PA,Andersson-Assarsson JC.The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity, weight loss and resting metabolic rate.Biochem Biophys Res Commun2013;433:563-6 PMCID:PMC3639367

[16] Bhandari M,Buchwald JN.Bariatric Metabolic Surgery Standardization (BMSS) Working GroupStandardization of bariatric metabolic procedures: world consensus meeting statement.Obes Surg2019;29:309-45

[17] Diabetes Association. 1. Improving care and promoting health in populations: standards of medical care in diabetes-2020.Diabetes Care2020;43:S7-S13

[18] Grundy SM,Daniels SR.American Heart Association, National Heart, Lung, and Blood InstituteDiagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.Circulation2005;112:2735-52

[19] Meissburger B,Röder E,Wolfrum C.Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans.Diabetologia2011;54:1468-79

[20] Szántó M.The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism.Genes Dev2020;34:321-40 PMCID:PMC7050491

[21] Tinahones FJ,Murri M.Caspase induction and BCL2 inhibition in human adipose tissue: a potential relationship with insulin signaling alteration.Diabetes Care2013;36:513-21 PMCID:PMC3579349

[22] McQueen AE,Yan K.The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure.J Biol Chem2017;292:16122-34 PMCID:PMC5625043

[23] van Zutphen T,Yang J.FXR overexpression alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements.J Lipid Res2019;60:1547-61 PMCID:PMC6718433

[24] Barchetta I,Capoccia D.Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity.Nutrients2018;10:526 PMCID:PMC5946311

[25] McQueen AE,Wang JC.Fighting obesity by targeting factors regulating beige adipocytes.Curr Opin Clin Nutr Metab Care2018;21:437-43 PMCID:PMC6196736

[26] Aryal B,Zhang X.Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis.JCI Insight2018;3:97918 PMCID:PMC5926923

[27] Wensveen FM,Šestan M,Polić B.The "Big Bang" in obese fat: events initiating obesity-induced adipose tissue inflammation.Eur J Immunol2015;45:2446-56

[28] Verboven K,Gaens K.Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans.Sci Rep2018;8:4677 PMCID:PMC5856747

[29] Barchetta I,Ciccarelli G,Cavallo MG.Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation.J Endocrinol Invest2019;42:1257-72

[30] Cariou B,Duran-Sandoval D.The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice.J Biol Chem2006;281:11039-49