Central anorexigenic actions of bile acids are mediated by TGR5
Nat Metab. 2021-05-01; 3(5): 595-603
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Perino A(1), Velázquez-Villegas LA(1)(2), Bresciani N(1), Sun Y(1), Huang Q(1), Fénelon VS(3), Castellanos-Jankiewicz A(3), Zizzari P(3), Bruschetta G(4), Jin S(5), Baleisyte A(6), Gioiello A(7), Pellicciari R(8), Ivanisevic J(9), Schneider BL(10), Diano S(4)(5), Cota D(3), Schoonjans K(11).
(1)Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
(2)Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F., Mexico.
(3)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300, Bordeaux, France.
(4)Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
(5)Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA.
(6)Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
(7)Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
(8)TES Pharma S.r.l., Perugia, Italy.
(9)Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
(10)Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne, Geneva, Switzerland.
(11)Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. .
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 brain1, 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 BAs2 and an established regulator of peripheral metabolism3-8. 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.