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 path...

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Published in:Cell metabolism 2021-07, Vol.33 (7), p.1483-1492.e10
Main Authors: Castellanos-Jankiewicz, Ashley, Guzmán-Quevedo, Omar, Fénelon, Valérie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlène, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Bäckhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, Cota, Daniela
Format: Article
Language:English
Subjects:
Animals
bile acids
Bile Acids and Salts - metabolism
body weight
Body Weight - genetics
diet
energy expenditure
Energy Metabolism - genetics
food intake
GPBAR1
HEK293 Cells
Humans
hypothalamus
Hypothalamus - metabolism
Life Sciences
Mice
Mice, Inbred C57BL
Mice, Obese
Mice, Transgenic
obesity
Obesity - genetics
Obesity - metabolism
Obesity - prevention & control
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - physiology
sympathetic nervous system
TGR5
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Summary: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. [Display omitted] •Diet-induced obesity induces changes in the hypothalamic BA-TGR5 system•Central TGR5 agonism reduces obesity by activating the sympathetic nervous system•Hypothalamic TGR5 protects from the onset and worsening of diet-induced obesity•Hypothalamic TGR5 participates in the anti-obesity effects of BA supplementation Castellanos-Jankiewicz et al. demonstrate that activation of central TGR5 signaling counteracts diet-induced obesity, whereas genetic downregulation of hypothalamic TGR5 promotes it. These effects involve modulation of food intake and energy expenditure through the sympathetic nervous system, revealing a long-range bile acid-dependent hypothalamic mechanism contributing to weight regulation in obesity.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2021.04.009