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Satiety induced by bile acids is mediated via vagal afferent pathways
Xiaoyin Wu, … , Shi-Yi Zhou, Chung Owyang
Xiaoyin Wu, … , Shi-Yi Zhou, Chung Owyang
Published July 23, 2020
Citation Information: JCI Insight. 2020;5(14):e132400. https://doi.org/10.1172/jci.insight.132400.
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Research Article Gastroenterology

Satiety induced by bile acids is mediated via vagal afferent pathways

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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.

Authors

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

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Figure 2

BA and CCK have a synergistic effect on neuronal activation in the NG.

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BA and CCK have a synergistic effect on neuronal activation in the NG.
(...
(A) Infusion of 0.1 μg, 0.5 μg, 1 μg, and 10 μg/kg DCA via the superior mesenteric artery showed a dose-dependent increase in the firing rate of vagal afferent neurons in NG. There was a threshold effect seen with a dose of 0.5 μg/kg required for neuronal firing to occur. Right panel shows summarized data. (B) A subthreshold dose of DCA (0.1 μg/kg) combined with CCK-8 (0.0057 μg/kg) resulted in a synergistic effect on vagal afferent neuronal firing compared with either DCA (0.1 μg/kg) alone or CCK-8 (0.0057 μg/kg) alone. Right panel shows summarized data. A and B show representative recordings of neuronal firing; firing rates per every 10 seconds were determined by analysis using Spike 2 software. *P < 0.05, **P < 0.01 compared with basal firing rates. Forty-nine units from 5 rats were recorded. Mann-Whitney U test. (C) Total serum bile acid concentration was measured before and after different doses of DCA injection. One-way ANOVA with Tukey’s test. n = 8. (D) Total serum bile acid concentration was measured in rats fed with either regular chow or high-fat diet (HFD, 58% kcal fat) after fasting for 6 hours. Unpaired 2-tailed Student’s t test. n = 8. (E) Rats were fasted for 6 hours. Serum DCA concentration was measured in rats fed with regular chow, HFD, or regular chow with intravenous injection of DCA (10 μg/kg, blood was withdrawn 5 minutes after injection). One-way ANOVA with Tukey’s test. n = 5. Doses of DCA and CCK-8 are expressed as micrograms per kilogram.

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