Satiety induced by bile acids is mediated via vagal afferent pathways
Xiaoyin Wu, Ji-Yao Li, Allen Lee, Yuan-Xu Lu, Shi-Yi Zhou, Chung Owyang
Xiaoyin Wu, Ji-Yao Li, Allen Lee, Yuan-Xu Lu, Shi-Yi Zhou, Chung Owyang
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Research Article Gastroenterology

Satiety induced by bile acids is mediated via vagal afferent pathways

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 8

DCA reduces food intake while silencing of TGR5 and CCK-ARs enhances spontaneous feeding.

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DCA reduces food intake while silencing of TGR5 and CCK-ARs enhances spo...
(A) Dark phase spontaneous food intake was measured hourly for 3 hours after intravenous injection of DCA (1 μg/kg). Cumulative food intake significantly decreased at 1, 2, and 3 hours after DCA administration compared with saline (2-way ANOVA with post hoc Tukey’s test, *P < 0.05, **P < 0.01, n = 8). (B) One- to three-hour dark phase spontaneous food intake 5 days after knockdown with siRNAs in NG. Silencing of TGR5 increased feeding in the first 3 hours by 18% ± 2%, silencing of CCK-AR increased feeding in the first 3 hours by 13.5% ± 2.4%, while silencing of both TGR5 and CCK-AR enhanced feeding by 37% ± 4% (2-way ANOVA with post hoc Tukey’s test, *P < 0.05, **P < 0.01, n = 8–13). (C) Twenty-four-hour food intake 5 days after siRNAs. Silencing of TGR5 or CCK-AR increased daily food intake by 8% ± 0.2% and 6% ± 0.2%, respectively, while silencing of both TGR5 and CCK AR enhanced daily food intake by 14% ± 0.2% (1-way ANOVA with post hoc Tukey’s test, *P < 0.05, **P < 0.01, n = 6–10). (D) Total body weight gain (g) 6 days after siRNAs. Silencing of TGR5 or CCK-AR resulted in additional body weight gain compared with control siRNA. Silencing of both TGR5 and CCK-AR enhanced body weight gain further (1-way ANOVA with Tukey’s test *P < 0.05, n = 6–10). (E) Compared with control siRNA, silencing of TGR5 abolished DCA-induced (1 μg/kg, iv) inhibition of feeding, which was measured at day 6 after silencing (2-way ANOVA with post hoc Tukey’s test, *P < 0.05, **P < 0.01, n = 8–13).