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PPAR-? activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic ?-cells.
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ABSTRACT: Background
It has been reported that peroxisome proliferator-activated receptor (PPAR)-? and their synthetic ligands have direct effects on pancreatic ?-cells. We investigated whether PPAR-? activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic ?-cells.Methods
Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ) and/or adenoviral PPAR-? overexpression. OLETF rats were treated with RGZ.Results
PPAR-? activation with RGZ and/or adenoviral PPAR-? overexpression increased free fatty acid (FFA) receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-? activation. In addition, the ?-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and ?-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-? antagonist. Finally, PPAR-? activation up-regulated ?-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets.Conclusion
These observations suggest that PPAR-? activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and ?-cell gene expression through GPR40 and GLUT2 gene up-regulation.
SUBMITTER: Kim HS
PROVIDER: S-EPMC3553172 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.
PloS one 20130123 1
<h4>Background</h4>It has been reported that peroxisome proliferator-activated receptor (PPAR)-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells.<h4>Methods</h4>Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ) and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ.<h4>Results</h4>PPAR-γ act ...[more]