2. Academic Validation
  3. Hypothalamic bile acid-TGR5 signaling protects from obesity

Hypothalamic bile acid-TGR5 signaling protects from obesity

  • Cell Metab. 2021 Jul 6;33(7):1483-1492.e10. doi: 10.1016/j.cmet.2021.04.009.
Ashley Castellanos-Jankiewicz 1,  Omar Guzmán-Quevedo 2,  Valérie S Fénelon 1,  Philippe Zizzari 1,  Carmelo Quarta 1,  Luigi Bellocchio 1,  Anne Tailleux 3,  Julie Charton 4,  Daniela Fernandois 5,  Marcus Henricsson 6,  Catherine Piveteau 7,  Vincent Simon 1,  Camille Allard 1,  Sandrine Quemener 3,  Valentine Guinot 3,  Nathalie Hennuyer 3,  Alessia Perino 8,  Alexia Duveau 1,  Marlène Maitre 1,  Thierry Leste-Lasserre 1,  Samantha Clark 1,  Nathalie Dupuy 1,  Astrid Cannich 1,  Delphine Gonzales 1,  Benoit Deprez 4,  Gilles Mithieux 9,  David Dombrowicz 3,  Fredrik Bäckhed 10,  Vincent Prevot 5,  Giovanni Marsicano 1,  Bart Staels 3,  Kristina Schoonjans 8,  Daniela Cota 11
Affiliations

Affiliations

  • 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: [email protected].
PMID: 33887197 DOI: 10.1016/j.cmet.2021.04.009
Abstract

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.

Keywords

GPBAR1; TGR5; bile acids; body weight; diet; energy expenditure; food intake; hypothalamus; obesity; sympathetic nervous system.

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