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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 ?g/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.

SUBMITTER: Wu X

PROVIDER: S-EPMC7453905 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Wu Xiaoyin X Li Ji-Yao JY Lee Allen A Lu Yuan-Xu YX Zhou Shi-Yi SY Owyang Chung C

JCI insight 20200723 14

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 ...[more]

PMID: 32699194

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Project description:Bile acids (BAs) are molecules derived from cholesterol that are involved in dietary fat absorption. New evidence supports an additional role for BAs as regulators of brain function. Sterols such as cholesterol interact with monoamine transporters, including the dopamine (DA) transporter (DAT) which plays a key role in DA neurotransmission and reward. This study explores the interactions of the BA, obeticholic acid (OCA), with DAT and characterizes the regulation of DAT activity via both electrophysiology and molecular modeling. We expressed murine DAT (mDAT) in Xenopus laevis oocytes and confirmed its functionality. Next, we showed that OCA promotes a DAT-mediated inward current that is Na+-dependent and not regulated by intracellular calcium. The current induced by OCA was transient in nature, returning to baseline in the continued presence of the BA. OCA also transiently blocked the DAT-mediated Li+-leak current, a feature that parallels DA action and indicates direct binding to the transporter in the absence of Na+. Interestingly, OCA did not alter DA affinity nor the ability of DA to promote a DAT-mediated inward current, suggesting that the interaction of OCA with the transporter is non-competitive, regarding DA. Docking simulations performed for investigating the molecular mechanism of OCA action on DAT activity revealed two potential binding sites. First, in the absence of DA, OCA binds DAT through interactions with D421, a residue normally involved in coordinating the binding of the Na+ ion to the Na2 binding site (Borre et al., J. Biol. Chem., 2014, 289, 25764-25773; Cheng and Bahar, Structure, 2015, 23, 2171-2181). Furthermore, we uncover a separate binding site for OCA on DAT, of equal potential functional impact, that is coordinated by the DAT residues R445 and D436. Binding to that site may stabilize the inward-facing (IF) open state by preventing the re-formation of the IF-gating salt bridges, R60-D436 and R445-E428, that are required for DA transport. This study suggests that BAs may represent novel pharmacological tools to regulate DAT function, and possibly, associated behaviors.

Project description:Vagal afferent neurons (VAN), located in the nodose ganglion (NG) innervate the gut and terminate in the nucleus of solitary tract (NTS) in the brainstem. They are the primary sensory neurons integrating gut-derived signals to regulate meal size. Chronic high-fat diet (HFD) consumption impairs vagally mediated satiety, resulting in overfeeding. There is evidence that HFD consumption leads to alterations in both vagal nerve function and structural integrity. HFD also leads to marked gut microbiota dysbiosis; in rodent models, dysbiosis is sufficient to induce weight gain. In this study, we investigated the effect of microbiota dysbiosis on gut-brain vagal innervation independently of diet. To do so, we recolonized microbiota-depleted rats with gastrointestinal (GI) contents isolated from donor animals fed either a HFD (45 or 60% fat) or a low fat diet (LFD, 13% fat). We used two different depletion models while maintaining the animals on LFD: 1) conventionally raised Fischer and Wistar rats that underwent a depletion paradigm using an antibiotic cocktail and 2) germ free (GF) raised Fischer rats. Following recolonization, receiver animals were designated as ConvLF and ConvHF. Fecal samples were collected throughout these studies and analyzed via 16S Illumina sequencing. In both models, bacteria that were identified as characteristic of HFD were successfully transferred to recipient animals. Three weeks post-colonization, ConvHF rats showed significant increases in ionized calcium-binding adapter molecule-1 (Iba1) positive immune cells in the NG compared to ConvLF animals. Additionally, using isolectin B4 (IB4) staining to identify c-fibers, we found that, compared to ConvLF animals, ConvHF rats displayed decreased innervation at the level of the medial NTS; c-fibers at this level are believed to be primarily of vagal origin. This alteration in vagal structure was associated with a loss in satiety induced by the gut peptide cholecystokinin (CCK). Increased presence of immunocompetent Iba1+ cells along the gut-brain axis and alterations in NTS innervation were still evident in ConvHF rats compared to ConvLF animals 12 weeks post-colonization and were associated with increases in food intake and body weight (BW). We conclude from these data that microbiota dysbiosis can alter gut-brain vagal innervation, potentially via recruitment and/or activation of immune cells.

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

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

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