期刊
DIABETES
卷 69, 期 4, 页码 614-623出版社
AMER DIABETES ASSOC
DOI: 10.2337/db19-0764
关键词
-
资金
- long-term Federation of European Biochemical Societies fellowship
- Wellcome Trust [106262/Z/14/Z, 106263/Z/14/Z]
- UK Medical Research Council [MRC_MC_UU_12012/3]
- Novo Nordisk Foundation [NNF10CC1016515, NNF14OC0016798]
- University of Copenhagen Challenge [NNF15OC0013655]
- Swiss National Science Foundation (Sinergia) [CRSII5_180317/1_125487]
- Ecole Polytechnique Federale de Lausanne (EPFL)
- MRC [MC_UU_12012/3, MC_UU_00014/3, MC_UU_00014/5] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据