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  4. Central anorexigenic actions of bile acids are mediated by TGR5
 
research article

Central anorexigenic actions of bile acids are mediated by TGR5

Perino, Alessia  
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Velazquez-Villegas, Laura A.  
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Bresciani, Nadia  
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May 1, 2021
Nature Metabolism

Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs and an established regulator of peripheral metabolism. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system. Bile acids are shown to enter the brain and regulate short-term reductions in food intake after a meal by inhibiting neuropeptide release from agouti-related peptide/neuropeptide Y neurons.

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Type
research article
DOI
10.1038/s42255-021-00398-4
Web of Science ID

WOS:000656451600005

Author(s)
Perino, Alessia  
Velazquez-Villegas, Laura A.  
Bresciani, Nadia  
Sun, Yu  
Huang, Qingyao  
Fenelon, Valerie S.
Castellanos-Jankiewicz, Ashley
Zizzari, Philippe
Bruschetta, Giuseppe
Jin, Sungho
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Date Issued

2021-05-01

Published in
Nature Metabolism
Volume

3

Issue

5

Start page

595

End page

603

Subjects

Endocrinology & Metabolism

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Endocrinology & Metabolism

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glucagon-like peptide-1

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area postrema

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agrp neurons

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receptor

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rat

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activation

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leptin

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cortex

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gaba

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPSCHOONJANS  
Available on Infoscience
June 19, 2021
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/179320
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