期刊
CELL METABOLISM
卷 33, 期 7, 页码 1483-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2021.04.009
关键词
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资金
- INSERM
- LabEX BRAIN [ANR-10-LABX-43]
- FRM [DGE20061007758]
- Aquitaine Region
- French Societies of Endocrinology, Nutrition, and Diabetes
- Fondation Francophone pour la Recherche sur le Diabete (FFRD) - Federation Francaise des Diabetiques (AFD)
- AstraZeneca
- Eli Lilly
- Merck Sharp Dohme
- Novo Nordisk
- Sanofi
- Mexican CONACYT PhD fellowship
- Mexican CONACYT postdoc fellowship
- AXA postdoctoral fellowship
- ERC [810331, 694717]
- Labex EGID [ANR10-LABX-46]
- Swiss National Science Foundation (SNSF) [310030_189178]
- KG Jebsen Foundation
- [ANR-10-INBS-04]
- [ANR-13-BSV4-0006 NeuroNutriSens]
- [ANR-17-CE14-0007 BABrain]
- [ANR-10-EQX-008-1 OPTOPATH]
- [ANR-18-CE14-0029 MitObesity]
- [ANR-20-CE14-0046]
- Swiss National Science Foundation (SNF) [310030_189178] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [810331] Funding Source: European Research Council (ERC)
Activation of hypothalamic TGR5 signaling reduces body weight and fat mass by promoting negative energy balance, counteracting diet-induced obesity. Conversely, downregulation of hypothalamic TGR5 expression may contribute to the development of obesity. These findings highlight the important role of hypothalamic TGR5 signaling in the pathophysiology of 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.
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