Satiety induced by bile acids is mediated via vagal afferent pathways.

Xiaoyin Wu,Ji-Yao Li,Yuan-Xu Lu,Allen Lee,Shi-Yi Zhou,Chung Owyang

doi:10.1172/jci.insight.132400

Abstract

The aim of this study was to elucidate the role and the pathways used by bile acid receptor TGR5 in transmitting satiety signals. We showed TGR5 colocalized with cholecystokinin type A (CCK-A) receptors in a subpopulation of rat nodose ganglia (NG) neurons. Intra-arterial injection of deoxycholic acid (DCA) dose-dependently increased firing rate in NG while a subthreshold dose of DCA and CCK-8 increased firing rates synergistically. TGR5-specific agonist oleanolic acid induced NG neuronal firing in a dose-dependent manner. However, the same units did not respond to GW4064, a nuclear receptor-specific agonist. Quantity of DCA-activated neurons in the hypothalamus was determined by c-Fos expression. Combining DCA and CCK-8 caused a 4-fold increase in c-Fos activation. In the arcuate nucleus, c-Fos-positive neurons coexpressed cocaine and amphetamine regulated transcript and proopiomelanocortin. DCA-induced c-Fos expression was eliminated following truncal vagotomy or silencing of TGR5 in the NG. Feeding studies showed intravenous injection of 1 μg/kg of DCA reduced food intake by 12% ± 3%, 24% ± 5%, and 32% ± 6% in the first 3 hours, respectively. Silencing of TGR5 or CCK-A receptor in the NG enhanced spontaneous feeding by 18% ± 2% and 13.5% ± 2.4%, respectively. When both TGR5 and CCK-A receptor were silenced, spontaneous feeding was enhanced by 37% ± 4% in the first 3 hours, suggesting that bile acid may have a physiological role in regulating satiety. Working in concert with CCK, bile acid synergistically enhanced satiety signals to reduce spontaneous feeding.

Highlights

TGR5, known as M-BAR, GPBAR, GPR131, or BG37, is a G protein–coupled receptor containing 7 transmembrane domains that is activated by bile acids
TGR5 colocalizes with cholecystokinin type A (CCK-A) receptor in nodose ganglia (NG) neurons, which are activated by bile acid and CCK-8
Using reverse transcription PCR (RT-PCR), we showed that TGR5 mRNA was expressed in rat NG (Figure 1E)

Summary

Introduction

TGR5, known as M-BAR, GPBAR, GPR131, or BG37, is a G protein–coupled receptor containing 7 transmembrane domains that is activated by bile acids. Watanabe et al showed that administration of bile acids prevented high fat diet–induced obesity and increased energy expenditure in brown adipose tissue in mice [6]. These effects were mediated by TGR5, which activates thyroid hormone–activating enzyme iodothyronine deiodinase type II in brown adipose tissue (BAT). Maruyama et al observed that female TGR5–/– mice weighed more and had a higher fat content, compared with the WT [7]. It is not known whether TGR5 is involved in the regulation of food intake

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