Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.

Rune Ehrenreich Kuhre; Nicolai Jacob Wewer Albrechtsen; Olav Larsen; Sara Lind Jepsen; Emilie Balk-Møller; Daniel Bjørklund Andersen; Carolyn F. Deacon; Kristina Schoonjans; Frank  Reimann; Fiona M. Gribble; Reidar Albrechtsen; Bolette Hartmann; Mette Rosenkilde; Jens Juul Holst

doi:10.1016/j.molmet.2018.03.007

Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.

Rune Ehrenreich Kuhre, Nicolai Jacob Wewer Albrechtsen, Olav Larsen, Sara Lind Jepsen, Emilie Balk-Møller, Daniel Bjørklund Andersen, Carolyn F. Deacon, Kristina Schoonjans, Frank Reimann, Fiona M. Gribble, Reidar Albrechtsen, Bolette Hartmann, Mette Rosenkilde, Jens Juul Holst

Endocrinology and Metabolism

60 Citations (Scopus)

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Abstract

OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. RESULTS: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)>Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on α-cells or β-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. CONCLUSION: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5.

Original language	English
Journal	Molecular Metabolism
Volume	11
Pages (from-to)	84-95
Number of pages	12
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2018.03.007
Publication status	Published - 2018

Keywords

Bile-acids
GLP-1
Insulin
Neurotensin
PYY
TGR5

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10.1016/j.molmet.2018.03.007Licence: CC BY-NC-ND

Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreasFinal published version, 2.69 MBLicence: CC BY-NC-ND

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Kuhre, R. E., Albrechtsen, N. J. W., Larsen, O., Jepsen, S. L., Balk-Møller, E., Andersen, D. B., Deacon, C. F., Schoonjans, K., Reimann, F., Gribble, F. M., Albrechtsen, R., Hartmann, B., Rosenkilde, M., & Holst, J. J. (2018). Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Molecular Metabolism, 11, 84-95. https://doi.org/10.1016/j.molmet.2018.03.007

Kuhre, RE , Albrechtsen, NJW , Larsen, O , Jepsen, SL, Balk-Møller, E, Andersen, DB , Deacon, CF, Schoonjans, K, Reimann, F, Gribble, FM, Albrechtsen, R , Hartmann, B , Rosenkilde, M & Holst, JJ 2018, 'Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.', Molecular Metabolism, vol. 11, pp. 84-95. https://doi.org/10.1016/j.molmet.2018.03.007

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title = "Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.",

abstract = "OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. RESULTS: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)>Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on α-cells or β-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. CONCLUSION: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5.",

keywords = "Bile-acids, GLP-1, Insulin, Neurotensin, PYY, TGR5",

author = "Kuhre, {Rune Ehrenreich} and Albrechtsen, {Nicolai Jacob Wewer} and Olav Larsen and Jepsen, {Sara Lind} and Emilie Balk-M{\o}ller and Andersen, {Daniel Bj{\o}rklund} and Deacon, {Carolyn F.} and Kristina Schoonjans and Frank Reimann and Gribble, {Fiona M.} and Reidar Albrechtsen and Bolette Hartmann and Mette Rosenkilde and Holst, {Jens Juul}",

year = "2018",

doi = "10.1016/j.molmet.2018.03.007",

language = "English",

volume = "11",

pages = "84--95",

journal = "Molecular Metabolism",

issn = "2212-8778",

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TY - JOUR

T1 - Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.

AU - Kuhre, Rune Ehrenreich

AU - Albrechtsen, Nicolai Jacob Wewer

AU - Larsen, Olav

AU - Jepsen, Sara Lind

AU - Balk-Møller, Emilie

AU - Andersen, Daniel Bjørklund

AU - Deacon, Carolyn F.

AU - Schoonjans, Kristina

AU - Reimann, Frank

AU - Gribble, Fiona M.

AU - Albrechtsen, Reidar

AU - Hartmann, Bolette

AU - Rosenkilde, Mette

AU - Holst, Jens Juul

PY - 2018

Y1 - 2018

N2 - OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. RESULTS: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)>Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on α-cells or β-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. CONCLUSION: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5.

AB - OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. RESULTS: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)>Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on α-cells or β-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. CONCLUSION: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5.

KW - Bile-acids

KW - GLP-1

KW - Insulin

KW - Neurotensin

KW - PYY

KW - TGR5

U2 - 10.1016/j.molmet.2018.03.007

DO - 10.1016/j.molmet.2018.03.007

M3 - Journal article

C2 - 29656109

SN - 2212-8778

VL - 11

SP - 84

EP - 95

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -

Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas.

Abstract

Keywords

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