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This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/E390    most recent 00016.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Parton, L. E. Articles by Rutter, G. A. Search for Related Content PubMed PubMed Citation Articles by Parton, L. E. Articles by Rutter, G. A.

Impact of PPAR overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

¹Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD United Kingdom; and ²GlaxoSmithKline, Department of Metabolic Diseases, Research Triangle Park, North Carolina 27709

Submitted 9 January 2004 ; accepted in final form 26 April 2004

Peroxisome proliferator-activated receptor- (PPAR) serves as a target for the thiazolidinedione class of antidiabetic drugs and is an important regulator of adipose tissue differentiation. By contrast, the principal target genes for PPAR 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, 1 and 2, are expressed in primary rat islets and are upregulated by overexpresssion of the lipogenic transcription factor sterol response element-binding protein 1c. Unexpectedly, however, oligonucleotide microarray analysis demonstrates that graded activation of PPAR achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPAR1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPAR1 reduces islet triglyceride levels and enhances the oxidation of exogenous palmitate while decreasing glucose oxidation, cellular ATP content, and glucose-, but not depolarization-stimulated, insulin secretion. We conclude that, in the context of the pancreatic islet, the principal response to PPAR expression and activation is the activation of genes involved in the disposal, rather than the synthesis, of fatty acids. Although fatty acid oxidation may have beneficial effects on -cell function in the longer term by countering -cell "lipotoxicity," the acute response to this metabolic shift is a marked inhibition of insulin secretion.

-cell; insulin; secretion; peroxisome proliferator-activated receptor-; sterol regulatory element-binding protein-1c; thiazolidinedione; glucolipotoxicity

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