Hypothalamic bile acid-TGR5 signaling protects from obesity.

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 Elsevier Inc. All rights reserved.

Citation

Ashley Castellanos-Jankiewicz, Omar Guzmán-Quevedo, Valérie S Fénelon, Philippe Zizzari, Carmelo Quarta, Luigi Bellocchio, Anne Tailleux, Julie Charton, Daniela Fernandois, Marcus Henricsson, Catherine Piveteau, Vincent Simon, Camille Allard, Sandrine Quemener, Valentine Guinot, Nathalie Hennuyer, Alessia Perino, Alexia Duveau, Marlène Maitre, Thierry Leste-Lasserre, Samantha Clark, Nathalie Dupuy, Astrid Cannich, Delphine Gonzales, Benoit Deprez, Gilles Mithieux, David Dombrowicz, Fredrik Bäckhed, Vincent Prevot, Giovanni Marsicano, Bart Staels, Kristina Schoonjans, Daniela Cota. Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell metabolism. 2021 Jul 06;33(7):1483-1492.e10

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PMID: 33887197

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