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

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  • 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
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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
Article numberdb190764
JournalDiabetes
Volume69
Issue number4
Pages (from-to)614-623
Number of pages10
ISSN0012-1797
DOIs
Publication statusPublished - Apr 2020

    Research areas

  • 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

ID: 59293715