Open AccessCentral anorexigenic actions of bile acids are mediated by TGR5
Author(s) -
Alessia Perino,
Laura A. Velázquez-Villegas,
Nadia Bresciani,
Yu Sun,
Qingyao Huang,
Valérie S. Fénelon,
Ashley Castellanos-Jankiewicz,
Philippe Zizzari,
Giuseppe Bruschetta,
SungHo Jin,
Aiste Baleisyte,
Antimo Gioiello,
Roberto Pellicciari,
Julijana Ivanišević,
Bernard L. Schneider,
Sabrina Diano,
Daniela Cota,
Kristina Schoonjans
Publication year - 2021
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-021-00398-4
Subject(s) - orexigenic , g protein coupled bile acid receptor , receptor , biology , neuropeptide , medicine , endocrinology , microbiology and biotechnology , neuropeptide y receptor , regulator , neuroscience , biochemistry , gene
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 1 , 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 2 and an established regulator of peripheral metabolism 3-8 . 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.