L-cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling
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L-cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling. / 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 J.P.; Schoonjans, Kristina; Bäckhed, Fredrik; Schwartz, Thue W.; Petersen, Natalia.
In: Diabetes, Vol. 69, No. 4, 04.2020, p. 614-623.Research output: Contribution to journal › Journal article › Research › peer-review
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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
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.
U2 - 10.2337/db19-0764
DO - 10.2337/db19-0764
M3 - Journal article
C2 - 32041793
AN - SCOPUS:85082147626
VL - 69
SP - 614
EP - 623
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -
ID: 243062169