TGR5 Expression Is Associated with Changes in the Heart and Urinary Bladder of Rats with Metabolic Syndrome

Chia-Chen Hsu ,Yingxiao Li,Kai‐Chun Cheng ,Juei‐Tang Cheng ,Ping-Hao Hsu ,Ho‐Shan Niu

doi:10.3390/life11070695

Abstract

Adipose-derived cytokines may contribute to the inflammation that occurs in metabolic syndrome (MetS). The Takeda G protein-coupled receptor (TGR5) regulates energy expenditure and affects the production of pro-inflammatory biomarkers in metabolic diseases. Etanercept, which acts as a tumor necrosis factor (TNF)-α antagonist, can also block the inflammatory response. Therefore, the interaction between TNF-α and TGR5 expression was investigated in rats with high-fat diet (HFD)-induced obesity. Heart tissues isolated from the HFD-induced MetS rats were analyzed. Changes in TGR5 expression were investigated with lithocholic acid (LCA) as the agonist. Betulinic acid (BA) was used to activate TGR5 in urinary bladders. LCA was more effective in the heart tissues of HFD-fed rats, although etanercept alleviated the function of LCA. STAT3 activation and higher TGR5 expression were observed in the heart tissues collected from HFD-fed rats. Thus, cardiac TGR5 expression is promoted by HFD through STAT3 activation in rats. Moreover, the urinary bladders of female rats fed a HFD showed a low response, which was reversed by etanercept. Relaxation by BA in the bladders was more marked in HFD-fed rats. The high TGR5 expression in HFD-fed rats was characterized using a mRNA assay, and the increased cAMP levels were found to be stimulated by BA in the isolated bladders. Therefore, TGR5 expression increases with a HFD in both the hearts and urinary bladders. Collectively, cytokine-medicated TGR5 activation was observed in the hearts and urinary bladders of rats.

Highlights

Takeda G protein-coupled receptor (TGR5) belongs to the G protein-coupled receptor (GPCR) superfamily [1]
It has been documented that cardiac TGR5 expression is promoted in type-1 diabetic rats [9], mainly due to hyperglycemia, which seems to be related to compensatory homeostasis
We found that betulinic acid induced an increase in cAMP more markedly in the urinary bladders isolated from high-fat diet (HFD)-fed rats than in those isolated from normal rats

Summary

Introduction

Takeda G protein-coupled receptor (TGR5) belongs to the G protein-coupled receptor (GPCR) superfamily [1]. In addition to the heart [2], TGR5 is expressed in other organs and is amenable to being targeted by bile acids in both healthy and diseased states [3]. TGR5 is a metabolic regulator, which is involved in inflammatory responses [4]. TGR5 activation induces cytoprotective changes in the heart [5,6]. Bile acid may stimulate cholinergic M2 receptors, which cause negative effects on myocardial contractility and heart rate [7]. TGR5 activation is introduced to provide benefits to cardiac function [8]. It has been documented that cardiac TGR5 expression is promoted in type-1 diabetic rats [9], mainly due to hyperglycemia, which seems to be related to compensatory homeostasis. TGR5 expression in other metabolic disorders remains unknown

Methods

Findings

Discussion

Conclusion