Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein–coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1–dependent and serotonin-mediated mechanism.

中文翻译：

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胆汁酸通过 GPBAR1、旁分泌 GLP-1 和血清素信号传导诱导 L 细胞分化


胰高血糖素样肽 1 (GLP-1) 模拟物是治疗 2 型糖尿病的有效药物，因此人们对增加内源性 GLP-1 分泌和 L 细胞丰度产生广泛兴趣。在这里，我们将 G 蛋白偶联胆汁酸受体 1 (GPBAR1) 确定为肠道 L 细胞分化的选择性调节剂。石胆酸和合成的 GPBAR1 激动剂 L3740 选择性增加小鼠和人类肠道类器官中的 L 细胞密度，并提高 GLP-1 分泌能力。 L3740 诱导 Gcg 和转录因子 Ngn3 和 NeuroD1 的表达。 L3740 还增加了 L 细胞数量和 GLP-1 水平，并改善了体内葡萄糖耐量。进一步的机制检查表明，L3740 对 L 细胞的作用需要完整的 GLP-1 受体和血清素 5-羟色胺受体 4 (5-HT4) 信号传导。重要的是，通过 5-HT4 的血清素信号传导模仿了 L3740 的作用，作用于 GLP-1 的下游。因此，GPBAR1 激动剂和其他强大的 GLP-1 促分泌剂通过旁分泌 GLP-1 依赖性和血清素介导的机制促进 L 细胞分化。