Central anorexigenic actions of bile acids are mediated by TGR5

Perino, Alessia; Velázquez-Villegas, Laura A.; Bresciani, Nadia; Sun, Yu; Huang, Qingyao; Fénelon, Valérie S.; Castellanos-Jankiewicz, Ashley; Zizzari, Philippe; Bruschetta, Giuseppe; Jin, Sung‐Ho; Baleisyte, Aiste; Gioiello, Antimo; Pellicciari, Roberto; Ivanišević, Julijana; Schneider, Bernard L.; Diano, Sabrina; Cota, Daniela; Schoonjans, Kristina

doi:10.1038/s42255-021-00398-4

Cited by 73 publications

(82 citation statements)

References 38 publications

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“…Receptors for BAs are present throughout the brain (Maruyama et al, 2002;Kawamata et al, 2003;Keitel et al, 2010;Huang et al, 2015;Perino et al, 2021) and evidence exists for their synthesis directly in the CNS (McMillin and DeMorrow, 2016;Mertens et al, 2017;Kiriyama and Nochi, 2019). This raises the possibility of physiologic roles for BAs other than acting as an adjuvant in fat absorption, such as regulators of CNS activity.…”

Section: Introductionmentioning

confidence: 99%

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Bile Acids Gate Dopamine Transporter Mediated Currents

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

“…BA concentrations vary in the body following a circadian rhythm and are highly influenced by the fasting vs fed state (Fiorucci et al, 2021;Perino et al, 2021). Changes in circulating BAs are also promoted by pathological alterations in liver functionality and metabolism (Fiorucci et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Bile Acids Gate Dopamine Transporter Mediated Currents

et al. 2021

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“…The metabolic improvements both through bariatric surgery [ 204 ] and Parabacteroides distasonis [ 201 ] can be simulated by targeted bile acid replacement. Finally, bile acids that reach the brain reduce food intake through activation of TGR5 receptors on agouti-related-peptide (AgRP) expressing inhibiting neurons [ 205 ].…”

Section: The Role Of the Microbiota-gut-brain Axis In Homeostatic And...mentioning

confidence: 99%

Microbiota and body weight control: Weight watchers within?

Boscaini

Leigh

Lavelle

et al. 2022

Molecular Metabolism

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“…Supplement of a bile acid mixture (taurocholic, glycocholic, deoxycholic, and cholic acid) exhibited an anti-obesity effect via the activation of hypothalamic TGR5 ( Castellanos-Jankiewicz et al, 2021 ). In terms of mechanism, hypothalamic TGR5 activation on the AgRP neuron, instead of the POMC neuron, decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release, and thus increases satiety and reduces food intake ( Perino et al, 2021 ).…”

Section: Microbiome and Metabolic Diseasesmentioning

confidence: 99%

Human Microbiome and Its Medical Applications

Zhang

Zhou

Xia

et al. 2022

Front. Mol. Biosci.

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The commensal microbiome is essential for human health and is involved in many processes in the human body, such as the metabolism process and immune system activation. Emerging evidence implies that specific changes in the microbiome participate in the development of various diseases, including diabetes, liver diseases, tumors, and pathogen infections. Thus, intervention on the microbiome is becoming a novel and effective method to treat such diseases. Synthetic biology empowers researchers to create strains with unique and complex functions, making the use of engineered microbes for clinical applications attainable. The aim of this review is to summarize recent advances about the roles of the microbiome in certain diseases and the underlying mechanisms, as well as the use of engineered microbes in the prevention, detection, and treatment of various diseases.

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Central anorexigenic actions of bile acids are mediated by TGR5

Cited by 73 publications

References 38 publications

Bile Acids Gate Dopamine Transporter Mediated Currents

Bile Acids Gate Dopamine Transporter Mediated Currents

Microbiota and body weight control: Weight watchers within?

Human Microbiome and Its Medical Applications

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