Abstract
The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119-/- mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119-/- mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55-/- mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable.
Keywords:
GPR119; GPR55; Glucagon-like peptide-1 (GLP-1); L-cells; Lysophosphatidylinositol (LPI); Mixed colonic preparation.
Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Line
-
Cell Line, Tumor
-
Cyclic AMP / metabolism
-
Cyclic AMP Response Element-Binding Protein / genetics
-
Cyclic AMP Response Element-Binding Protein / metabolism
-
Cyclic AMP-Dependent Protein Kinases / genetics
-
Cyclic AMP-Dependent Protein Kinases / metabolism
-
Enteroendocrine Cells / cytology
-
Enteroendocrine Cells / drug effects*
-
Enteroendocrine Cells / metabolism
-
Epithelial Cells / cytology
-
Epithelial Cells / drug effects
-
Epithelial Cells / metabolism
-
Gene Expression Regulation
-
Glucagon-Like Peptide 1 / genetics*
-
Glucagon-Like Peptide 1 / metabolism
-
Humans
-
Insulin / metabolism*
-
Insulin Secretion
-
Islets of Langerhans / drug effects
-
Islets of Langerhans / metabolism
-
Lysophospholipids / pharmacology*
-
Mice
-
Mice, Inbred C57BL
-
Mitogen-Activated Protein Kinase 1 / genetics
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Oleic Acids / pharmacology*
-
Primary Cell Culture
-
Receptors, Cannabinoid / deficiency
-
Receptors, Cannabinoid / genetics
-
Receptors, G-Protein-Coupled / deficiency
-
Receptors, G-Protein-Coupled / genetics*
-
Signal Transduction
Substances
-
Creb1 protein, mouse
-
Cyclic AMP Response Element-Binding Protein
-
GPR55 protein, mouse
-
Gpr119 protein, mouse
-
Insulin
-
Lysophospholipids
-
Oleic Acids
-
Receptors, Cannabinoid
-
Receptors, G-Protein-Coupled
-
lysophosphatidylinositol
-
Glucagon-Like Peptide 1
-
Cyclic AMP
-
Cyclic AMP-Dependent Protein Kinases
-
Mapk1 protein, mouse
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3