Zizzari Philippe, Castellanos-Jankiewicz Ashley, Yagoub Selma, Simon Vincent, Clark Samantha, Maître Marlene, Dupuy Nathalie, Leste-Lasserre Thierry, Gonzales Delphine, Schoonjans Kristina, Fénelon Valérie S, Cota Daniela
University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France.
Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
Mol Metab. 2025 Jan;91:102071. doi: 10.1016/j.molmet.2024.102071. Epub 2024 Nov 26.
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.
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.
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.
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.
腹内侧下丘脑的类固醇生成因子1（SF1）神经元在食物摄入、体重和葡萄糖代谢的调节中起关键作用。胆汁酸受体武田G蛋白偶联受体5（TGR5）在下丘脑中表达，它通过仍不清楚的神经元机制决定胆汁酸对食物摄入和体重的一些作用。在此，我们研究了TGR5在SF1神经元中对能量平衡和葡萄糖代谢调节的作用。
我们采用遗传学方法结合代谢表型分析和分子分析，以确定SF1神经元中TGR5缺失对进食模式、体重、身体组成、能量消耗和能量底物利用的影响，以及对葡萄糖处理和胰岛素敏感性可能的变化。
我们的研究结果表明，在标准饮食条件下，SF1神经元中的TGR5在食物摄入或体重调节中不起主要作用，但它参与了对急性寒冷暴露或高热量、高脂肪饮食的适应性进食反应，而能量消耗没有变化。值得注意的是，SF1神经元中的TGR5会阻碍葡萄糖代谢，因为该受体的缺失通过增强下丘脑和棕色脂肪组织中的胰岛素信号来改善全身葡萄糖摄取。
SF1神经元中的TGR5通过响应特定代谢信号以不同方式改变进食模式来促进饱腹感。这些研究还揭示了TGR5在SF1神经元中对全身胰岛素敏感性调节的新关键功能，为神经元TGR5在代谢调节中的作用提供了新的见解。
