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

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Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ 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 PPARγ, γ1 and γ2, 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 PPARγ achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPARγ1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPARγ1 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 PPARγ 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 β-cell function in the longer term by countering β-cell “lipotoxicity,” the acute response to this metabolic shift is a marked inhibition of insulin secretion.