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Am J Physiol Endocrinol Metab (May 4, 2004). doi:10.1152/ajpendo.00016.2004
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Submitted on January 9, 2004
Accepted on April 26, 2004

Impact of PPAR{gamma} over-expression and activation on pancreatic islet gene expression profile analysed with oligonucleotide microarrays

Laura E. Parton1, Frederique Diraison1, Suzanne E. Neill2, Sujoy K. Ghosh2, Mark A. Rubino2, John E. Bisi2, Celia P. Briscoe2, and Guy A. Rutter1*

1 Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol, United Kingdom
2 Department of Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, NC, USA

* To whom correspondence should be addressed. E-mail: g.a.rutter{at}bris.ac.uk.

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) serves as a target for the thiazolidinedione class of anti-diabetic drugs and is an important regulator of adipose tissue differentiation. By contrast, the principal target genes for PPAR{gamma} in the pancreatic islet, and the impact of their induction on insulin secretion, are largely undefined. Here, we show that mRNAs encoding both isoforms of rodent PPAR{gamma}, {gamma}1 and {gamma}2, are expressed in primary rat islets, and are up-regulated by over-expresssion of the lipogenic transcription factor, sterol response element binding protein 1c. Unexpectedly, however, oligonucleotide microarray analysis demonstrates that graded activation of PPAR{gamma} achieved with (A) the thiazolidinedione GW347845, (B) transduction with adenoviral PPAR{gamma}1, or (C) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPAR{gamma}1 reduces islet triglyceride levels and enhances the oxidation of exogenous palmitate, whilst decreasing glucose oxidation, cellular ATP content, and glucose-, but not depolarisation-stimulated, insulin secretion. We conclude that, in the context of the pancreatic islet, the principal response to PPAR{gamma} expression and activation is the activation of genes involved in the disposal, rather than the synthesis, of fatty acids. Whilst fatty acid oxidation may have beneficial effects on {beta}-cell function in the longer term by countering {beta}-cell "lipotoxicity", the acute response to this metabolic shift is a marked inhibition of insulin secretion (225 words).




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