L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling

Mari Lilith Lund, Giovanni Sorrentino, Kristoffer Lihme Egerod, Chantal Kroone, Brynjulf Mortensen, Filip Krag Knop, Frank Reimann, Fiona M Gribble, Daniel J Drucker, Eelco J P de Koning, Kristina Schoonjans, Fredrik Bäckhed, Thue W Schwartz, Natalia Petersen

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)614-623
Number of pages10
JournalDiabetes
Volume69
Issue number4
DOIs
Publication statusPublished - Apr 2020

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    Lund, M. L., Sorrentino, G., Egerod, K. L., Kroone, C., Mortensen, B., Knop, F. K., Reimann, F., Gribble, F. M., Drucker, D. J., de Koning, E. J. P., Schoonjans, K., Bäckhed, F., Schwartz, T. W., & Petersen, N. (2020). L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling. Diabetes, 69(4), 614-623. https://doi.org/10.2337/db19-0764