L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling
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Publication date
2020-04
Authors
Lund, Mari Lilith
Sorrentino, Giovanni
Egerod, Kristoffer Lihme
Kroone, Chantal
Mortensen, Brynjulf
Knop, Filip Krag
Reimann, Frank
Gribble, Fiona M
Drucker, Daniel J
de Koning, Eelco
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Article
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taverne
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.
Keywords
Animals, Bile Acids and Salts/pharmacology, Cell Differentiation/drug effects, Enteroendocrine Cells/drug effects, Female, Glucagon-Like Peptide 1/metabolism, Glucagon-Like Peptide-1 Receptor/metabolism, Humans, Jejunum/drug effects, Male, Mice, Paracrine Communication/drug effects, Receptors, G-Protein-Coupled/metabolism, Serotonin/metabolism, Signal Transduction/drug effects, Taverne, Internal Medicine, Endocrinology, Diabetes and Metabolism, Research Support, Non-U.S. Gov't, Journal Article
Citation
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, vol. 69, no. 4, pp. 614-623. https://doi.org/10.2337/db19-0764