Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada.
Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Endocrinology. 2021 Mar 1;162(3). doi: 10.1210/endocr/bqab002.
The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these 2 receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice, but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double knock-out animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these 2 receptors only minimally affects glucose homeostasis in vivo in mice.
游离脂肪酸受体 FFAR1（GPR40）和 FFAR4（GPR120）分别参与胰岛素分泌和胰岛素敏感性的调节。虽然 GPR120 和 GPR40 具有相似的配体，但很少有研究涉及这两种受体在葡萄糖稳态控制中的相互作用。在这里，我们生成了 GPR120 （Gpr120KO）或 GPR40 （Gpr40KO）缺失的小鼠，单独或组合缺失（Gpr120/40KO），并对正常饲料或高脂肪饮食喂养的雄性和雌性小鼠进行了代谢表型分析。我们评估了在单独或联合使用选择性 GPR120 和 GPR40 激动剂暴露于分离的小鼠胰岛时的胰岛素分泌。在正常饲料喂养后，删除任何一种受体都不会影响体重和能量摄入，尽管 Gpr120KO 雌性的脂肪量增加。Gpr120/40KO 小鼠的空腹血糖水平轻度升高，而 Gpr120KO 和 Gpr40KO 动物则以性别依赖的方式升高。雄性 Gpr120/40KO 小鼠和 Gpr120KO 雌性动物的口服葡萄糖耐量略降低，而胰岛素分泌和胰岛素敏感性不受影响。在高血糖钳夹中，雄性 Gpr120/40KO 小鼠的葡萄糖输注率较低，但胰岛素和 C 肽水平不受影响。在高脂肪喂养下，在单一或双重敲除动物中均未观察到葡萄糖耐量的变化。在野生型小鼠的分离胰岛中，选择性 GPR120 和 GPR40 激动剂的联合使用可使胰岛素分泌呈相加性增加。我们得出结论，尽管 GPR120 和 GPR40 的同时激活可增强离体的胰岛素分泌，但在体内，这两种受体的联合缺失对小鼠的葡萄糖稳态仅有微小影响。
