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Abstract
BackgroundIt 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.MethodsRat 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.ResultsPPAR-γ activation with RGZ and/or adenoviral PPAR-γ 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-γ activation. In addition, the β-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 β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-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.ConclusionThese observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.
Highlights
Peroxisome proliferator-activated receptor (PPAR)-c is a member of the nuclear receptor family that plays a crucial role in lipid and glucose homeostasis
Accumulating evidence indicates that GPR40 mediates the majority of both acute and chronic effects of free fatty acid (FFA) on insulin secretion, including the amplification of glucose-stimulated insulin secretion (GSIS) [21,23,24,25,26,27,28,29], and the receptor has been suggested to be involved in the control of cell proliferation via extracellular signal-related kinase (ERK), phosphoinositide 3-kinase (PI3K), and PKB
The stimulatory activities of 10 mM oleic or linoleic acids for 30 minutes on insulin secretion were detected more strongly when pretreated with 10 mM RGZ, indicating that FFAs amplify RGZ-stimulated insulin secretion from INS-1 cells (Fig. 1C)
Summary
Peroxisome proliferator-activated receptor (PPAR)-c is a member of the nuclear receptor family that plays a crucial role in lipid and glucose homeostasis. Some studies indicate that TZDs have direct effects on glucose-stimulated insulin secretion (GSIS) and pancreatic b-cell gene expression [3,4,5,6,7,8,9,10]. Accumulating evidence indicates that GPR40 mediates the majority of both acute and chronic effects of FFAs on insulin secretion, including the amplification of GSIS [21,23,24,25,26,27,28,29], and the receptor has been suggested to be involved in the control of cell proliferation via extracellular signal-related kinase (ERK), phosphoinositide 3-kinase (PI3K), and PKB signaling pathways [30]. It has been reported that peroxisome proliferator-activated receptor (PPAR)-c and their synthetic ligands have direct effects on pancreatic b-cells. We investigated whether PPAR-c activation stimulates insulin secretion through the upregulation of GPR40 in pancreatic b-cells
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