Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.
Mol Metab. 2023 Jun;72:101718. doi: 10.1016/j.molmet.2023.101718. Epub 2023 Apr 7.
Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21.
Circulating FGF21 levels were measured in fasted male C57BL/6J, neuronal GLP-1R knockout, β-cell GLP-1R knockout, and liver peroxisome proliferator-activated receptor alpha knockout mice treated acutely with liraglutide. To test the metabolic relevance of liver FGF21 in response to liraglutide, chow-fed control and liver Fgf21 knockout (Liv) mice were treated with vehicle or liraglutide in metabolic chambers. Body weight and composition, food intake, and energy expenditure were measured. Since FGF21 reduces carbohydrate intake, we measured body weight in mice fed matched diets with low- (LC) or high-carbohydrate (HC) content and in mice fed a high-fat, high-sugar (HFHS) diet. This was done in control and Liv mice and in mice lacking neuronal β-klotho (Klb) expression to disrupt brain FGF21 signaling.
Liraglutide increases FGF21 levels independently of decreased food intake via neuronal GLP-1R activation. Lack of liver Fgf21 expression confers resistance to liraglutide-induced weight loss due to attenuated reduction of food intake in chow-fed mice. Liraglutide-induced weight loss was impaired in Liv mice when fed HC and HFHS diets but not when fed a LC diet. Loss of neuronal Klb also attenuated liraglutide-induced weight loss in mice fed HC or HFHS diets.
Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in a dietary carbohydrate-dependent manner.
胰高血糖素样肽-1 受体（GLP-1R）激动剂（GLP-1RA）和成纤维细胞生长因子 21（FGF21）具有相似的代谢益处。GLP-1RA 诱导 FGF21，这促使我们研究 GLP-1RA 利拉鲁肽增加 FGF21 水平的机制以及利拉鲁肽诱导的 FGF21 的代谢相关性。
在急性给予利拉鲁肽的禁食雄性 C57BL/6J、神经元 GLP-1R 敲除、β细胞 GLP-1R 敲除和肝过氧化物酶体增殖物激活受体α敲除小鼠中测量循环 FGF21 水平。为了测试肝脏 FGF21 对利拉鲁肽反应的代谢相关性，在代谢室内用载体或利拉鲁肽处理正常饮食喂养的对照和肝脏 Fgf21 敲除（Liv）小鼠。测量体重和组成、食物摄入量和能量消耗。由于 FGF21 降低碳水化合物的摄入量，我们在给予低（LC）或高碳水化合物（HC）含量匹配饮食的小鼠以及给予高脂肪、高糖（HFHS）饮食的小鼠中测量体重。在对照和 Liv 小鼠以及缺乏神经元β-klotho（Klb）表达以破坏大脑 FGF21 信号的小鼠中进行了这项研究。
利拉鲁肽通过神经元 GLP-1R 激活增加 FGF21 水平，而不依赖于降低食物摄入量。缺乏肝脏 Fgf21 表达会导致利拉鲁肽诱导的体重减轻抵抗，因为在正常饮食喂养的小鼠中食物摄入量的减少减弱。在给予 HC 和 HFHS 饮食的 Liv 小鼠中，利拉鲁肽诱导的体重减轻受损，但在给予 LC 饮食的小鼠中没有受损。神经元 Klb 的缺失也减弱了给予 HC 或 HFHS 饮食的小鼠中利拉鲁肽诱导的体重减轻。
我们的研究结果支持 GLP-1R-FGF21 轴在以饮食碳水化合物依赖的方式调节体重方面的新作用。
