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Molecular and Cellular Biology, April 2009, p. 2053-2067, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01179-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Peroxisome Proliferator-Activated Receptor Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure

Carmella Evans-Molina,^1,2,3 Reiesha D. Robbins,³ Tatsuyoshi Kono,^1,2 Sarah A. Tersey,^2,4 George L. Vestermark,¹ Craig S. Nunemaker,⁵ James C. Garmey,⁵ Tye G. Deering,³ Susanna R. Keller,⁵ Bernhard Maier,^2,4 and Raghavendra G. Mirmira^1,2,4,6*

Department of Medicine,¹ Herman B. Wells Center for Pediatric Research,² Department of Pediatrics,⁴ Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202,⁶ Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908,³ Department of Medicine, University of Virginia, Charlottesville, Virginia 22908⁵

Received 26 July 2008/ Returned for modification 24 October 2008/ Accepted 6 February 2009

The nuclear receptor peroxisome proliferator-activated receptor (PPAR-) is an important target in diabetes therapy, but its direct role, if any, in the restoration of islet function has remained controversial. To identify potential molecular mechanisms of PPAR- in the islet, we treated diabetic or glucose-intolerant mice with the PPAR- agonist pioglitazone or with a control. Treated mice exhibited significantly improved glycemic control, corresponding to increased serum insulin and enhanced glucose-stimulated insulin release and Ca²⁺ responses from isolated islets in vitro. This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. The restoration of the Ins1/2 and Glut2 genes corresponded to a two- to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. Analysis of diabetic islets in vitro suggested that these effects resulting from the presence of the PPAR- agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 β cells with the PPAR- agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR- agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture.

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* Corresponding author. Mailing address: Indiana University School of Medicine, 635 Barnhill Drive, MS 2031B, Indianapolis, IN 46202. Phone: (317) 274-4145. Fax: (317) 274-4107. E-mail: rmirmira{at}iupui.edu

Published ahead of print on 23 February 2009.

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Molecular and Cellular Biology, April 2009, p. 2053-2067, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01179-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.