TY - JOUR
T1 - L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling
AU - Lund, Mari Lilith
AU - Sorrentino, Giovanni
AU - Egerod, Kristoffer Lihme
AU - Kroone, Chantal
AU - Mortensen, Brynjulf
AU - Knop, Filip Krag
AU - Reimann, Frank
AU - Gribble, Fiona M
AU - Drucker, Daniel J
AU - de Koning, Eelco J P
AU - Schoonjans, Kristina
AU - Bäckhed, Fredrik
AU - Schwartz, Thue W
AU - Petersen, Natalia
N1 - Funding Information:
Acknowledgments. The authors would like to thank Stine Lindberg Vedersø and Barbara Thaysen for technical assistance with the in vivo studies and Anna Sofie Husted for help with graphical design (all from the Novo Nordisk Foundation Center for Basic Metabolic Research). The authors gratefully acknowledge the support of the Core Facility for Integrated Microscopy (University of Copenhagen). Funding. G.S. is supported by a long-term Federation of European Biochemical Societies fellowship. Work in the Reimann/Gribble laboratory is supported by the Wellcome Trust (106262/Z/14/Z, 106263/Z/14/Z) and the UK Medical Research Council (MRC_MC_UU_12012/3). The Novo Nordisk Foundation Center for Basic Metabolic Research (https://www.metabol.ku.dk) is supported by an unconditional grant from the Novo Nordisk Foundation to the University of Copenhagen (NNF10CC1016515). The study was supported by the Novo Nordisk Foundation Challenge grant NNF14OC0016798 to F.B. and the University of Copenhagen Challenge grant NNF15OC0013655 to T.W.S. This work was supported by the Swiss National Science Foundation (Sinergia CRSII5_180317/1_125487) and the Ecole Polytechnique Fédérale de Lausanne (EPFL). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.L.L., G.S., K.L.E., C.K., and N.P. performed the research and analyzed and interpreted the experiments. M.L.L., F.B., T.W.S., and N.P. wrote the manuscript with input from all of the other authors. M.L.L., T.W.S., and N.P. conceived the study and designed experiments. B.M., F.K.K., and F.B. provided key samples and expertise. F.R., F.M.G., D.J.D., and K.S. provided essential mouse lines for the study and edited the manuscript. E.J.P.d.K., K.S., and F.B. designed studies. N.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 17th Copenhagen Bioscience Conference – Intestinal Organoids, Hillerød, Denmark, 29 September–2 October 2019.
Funding Information:
G.S. is supported by a long-term Federation of European Biochemical Societies fellowship. Work in the Reimann/Gribble laboratory is supported by the Wellcome Trust (106262/Z/14/Z, 106263/Z/14/Z) and the UK Medical Research Council (MRC_MC_UU_12012/3). The Novo Nordisk Foundation Center for Basic Metabolic Research (https://www.metabol.ku.dk) is supported by an unconditional grant from the Novo Nordisk Foundation to the University of Copenhagen (NNF10CC1016515). The study was supported by the Novo Nordisk Foundation Challenge grant NNF14OC0016798 to F.B. and the University of Copenhagen Challenge grant NNF15OC0013655 to T.W.S. This work was supported by the Swiss National Science Foundation (Sinergia CRSII5_180317/1_125487) and the Ecole Polytechnique Fédérale de Lausanne (EPFL).
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - Animals
KW - Bile Acids and Salts/pharmacology
KW - Cell Differentiation/drug effects
KW - Enteroendocrine Cells/drug effects
KW - Female
KW - Glucagon-Like Peptide 1/metabolism
KW - Glucagon-Like Peptide-1 Receptor/metabolism
KW - Humans
KW - Jejunum/drug effects
KW - Male
KW - Mice
KW - Paracrine Communication/drug effects
KW - Receptors, G-Protein-Coupled/metabolism
KW - Serotonin/metabolism
KW - Signal Transduction/drug effects
UR - https://www.scopus.com/pages/publications/85082147626
U2 - 10.2337/db19-0764
DO - 10.2337/db19-0764
M3 - Article
C2 - 32041793
SN - 0012-1797
VL - 69
SP - 614
EP - 623
JO - Diabetes
JF - Diabetes
IS - 4
ER -