Hypothalamic bile acid-TGR5 signaling protects from obesity.
Cell Metabolism. 2021-04-01; :
DOI: 10.1016/j.cmet.2021.04.009
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Castellanos-Jankiewicz A(1), Guzmán-Quevedo O(2), Fénelon VS(1), Zizzari P(1), Quarta C(1), Bellocchio L(1), Tailleux A(3), Charton J(4), Fernandois D(5),
Henricsson M(6), Piveteau C(7), Simon V(1), Allard C(1), Quemener S(3), Guinot V(3), Hennuyer N(3), Perino A(8), Duveau A(1), Maitre M(1), Leste-Lasserre T(1),
Clark S(1), Dupuy N(1), Cannich A(1), Gonzales D(1), Deprez B(4), Mithieux G(9), Dombrowicz D(3), Bäckhed F(10), Prevot V(5), Marsicano G(1), Staels B(3),
Schoonjans K(8), Cota D(11).
Author information:
(1)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.
(2)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France; Laboratory of Neuronutrition and Metabolic Disorders, Instituto Tecnológico Superior de Tacámbaro, 61650 Tacámbaro, Michoacán, Mexico; Pós-Graduação em Neuropsiquiatria e Ciências do Comportamento, Universidade
Federal de Pernambuco, 50732-970 Recife, Pernambuco, Brazil.
(3)University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59019 Lille, France.
(4)University of Lille, INSERM, Institut Pasteur de Lille, U1177 – Drugs and Molecules for Living Systems, EGID, F-59000 Lille, France.
(5)University of Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, F-59000, Lille, France.
(6)The Wallenberg Laboratory, Department of Molecular and Clinical Medicine,
Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45
Gothenburg, Sweden.
(7)University of Lille, INSERM, Institut Pasteur de Lille, U1177 – Drugs and
Molecules for Living Systems, F-59000 Lille, France.
(8)Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique
Fédérale de Lausanne, 1015 Lausanne, Switzerland.
(9)INSERM U1213 Nutrition, Diabetes and the Brain, University of Lyon 1 Faculté
de Médecine Lyon-Est, 69372 Lyon, France.
(10)The Wallenberg Laboratory, Department of Molecular and Clinical Medicine,
Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45
Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research,
Faculty of Health Sciences, University of Copenhagen, 2200 N Copenhagen, Denmark;
Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical
Physiology, Gothenburg, Sweden.
(11)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux,
France. Electronic address: .
Bile acids (BAs) improve metabolism and exert anti-obesity effects through the
activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral
tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic
BA signaling is implicated in body weight control and obesity pathophysiology
remains unknown. Here we show that hypothalamic BA content is reduced in
diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist
in these animals decreases body weight and fat mass by activating the sympathetic
nervous system, thereby promoting negative energy balance. Conversely, genetic
downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus
favors the development of obesity and worsens established obesity by blunting
sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the
anti-obesity action of dietary BA supplementation. Together, these findings
identify hypothalamic TGR5 signaling as a key mediator of a top-down neural
mechanism that counteracts diet-induced obesity.
Copyright © 2021. Published by Elsevier Inc.