PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells

被引:83
作者
Kim, Hyo-Sup [1 ]
Hwang, You-Cheol [2 ]
Koo, Seung-Hoi [3 ]
Park, Kyong Soo [4 ]
Lee, Myung-Shik [5 ]
Kim, Kwang-Won [5 ]
Lee, Moon-Kyu [5 ]
机构
[1] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Div Endocrinol & Metab, Seoul, South Korea
[2] Kyung Hee Univ, Sch Med, Kyung Hee Univ Hosp Gangdong, Div Endocrinol & Metab,Dept Med, Seoul, South Korea
[3] Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Seoul, South Korea
[4] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea
[5] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Endocrinol & Metab,Dept Med, Seoul, South Korea
关键词
PEROXISOME-PROLIFERATOR; METABOLIC DISEASE; RESPONSE ELEMENT; GENE-EXPRESSION; PROTEIN-KINASE; DIABETIC MICE; IN-VIVO; ROSIGLITAZONE; TROGLITAZONE; RELEASE;
D O I
10.1371/journal.pone.0050128
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: It has been reported that peroxisome proliferator-activated receptor (PPAR)-gamma and their synthetic ligands have direct effects on pancreatic beta-cells. We investigated whether PPAR-gamma activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic beta-cells. Methods: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ) and/or adenoviral PPAR-gamma overexpression. OLETF rats were treated with RGZ. Results: PPAR-gamma activation with RGZ and/or adenoviral PPAR-gamma 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-gamma activation. In addition, the beta-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 beta-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-gamma antagonist. Finally, PPAR-gamma activation up-regulated beta-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-gamma activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and beta-cell gene expression through GPR40 and GLUT2 gene up-regulation.
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页数:12
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