Impact of PPARgamma overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma 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 PPARgamma, gamma1 and gamma2, 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 PPARgamma achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPARgamma1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPARgamma1 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 PPARgamma 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 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.
Parton
Laura E
LE
Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD United Kingdom.
Diraison
Frédérique
F
Neill
Suzanne E
SE
Ghosh
Sujoy K
SK
Rubino
Mark A
MA
Bisi
John E
JE
Briscoe
Celia P
CP
Rutter
Guy A
GA
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D011189:Potassium Chloride; D005947:Glucose