TGR5 receptors in SF1-expressing neurons of the ventromedial hypothalamus regulate glucose homeostasis
Molecular Metabolism. 2025-01-01; 91: 102071
DOI: 10.1016/j.molmet.2024.102071
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Zizzari P(1), Castellanos-Jankiewicz A(1), Yagoub S(1), Simon V(1), Clark S(1),
Maître M(1), Dupuy N(1), Leste-Lasserre T(1), Gonzales D(1), Schoonjans K(2),
Fénelon VS(1), Cota D(3).
Author information:
(1)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000,
Bordeaux, France.
(2)Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique
Fédérale de Lausanne, 1015, Lausanne, Switzerland.
(3)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000,
Bordeaux, France. Electronic address: .
OBJECTIVE: Steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus
play key roles in the regulation of food intake, body weight and glucose
metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is
expressed in the hypothalamus, where it determines some of the actions of bile
acids on food intake and body weight through still poorly defined neuronal
mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation
of energy balance and glucose metabolism.
METHODS: We used a genetic approach combined with metabolic phenotyping and
molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on
meal pattern, body weight, body composition, energy expenditure and use of
energy substrates as well as on possible changes in glucose handling and insulin
sensitivity.
RESULTS: Our findings reveal that TGR5 in SF1 neurons does not play a major role
in the regulation of food intake or body weight under standard chow, but it is
involved in the adaptive feeding response to the acute exposure to cold or to a
hypercaloric, high-fat diet, without changes in energy expenditure. Notably,
TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor
improves whole-body glucose uptake through heightened insulin signaling in the
hypothalamus and in the brown adipose tissue.
CONCLUSIONS: TGR5 in SF1 neurons favours satiety by differently modifying the
meal pattern in response to specific metabolic cues. These studies also reveal a
novel key function for TGR5 in SF1 neurons in the regulation of whole-body
insulin sensitivity, providing new insight into the role played by neuronal TGR5
in the regulation of metabolism.
Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights
reserved.
DOI: 10.1016/j.molmet.2024.102071
PMCID: PMC11650306
PMID: 39603503
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.