A single element in the phosphoenolpyruvate carboxykinase gene mediates thiazolidinedione action specifically in adipocytes

Martine Glorian, Eric Duplus, Elmus G. Beale, Donald K. Scott, Daryl K. Granner, Claude Forest

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme in glyceroneogenesis, an important metabolic pathway that functions to restrain the release of non-esterified fatty acids (NEFAs) from adipocytes. The antidiabetic drugs known as thiazolidinediones (TZDs) are thought to achieve some of their benefits by lowering elevated plasma NEFAs. Moreover, peroxisome proliferator activated receptor γ (PPARγ) mediates the antidiabetic effects of TZDs, though many TZD responses appear to occur via PPARγ-independent pathways, PPARγ is required for adipocyte PEPCK expression, hence PEPCK could be a major target gene for the antidiabetic actions of TZDs. Here we used tissue culture and transfection assays to confirm that the TZD, rosiglitazone, stimulates PEPCK gene transcription specifically in adipocytes. We made the novel observation that this effect was by far the most rapid and robust among several other genes expressed in adipocytes. Adipocytes were transfected with a PEPCK/chloramphenicol acetyltransferase chimeric gene, in which either of the two previously discovered PPARγ/retinoid X receptor alpha response elements, PCK2 and gAF1/PCK1, had been inactivated by mutagenesis. We demonstrate that PCK2 alone is a bona fide thiazolidinedione response element. We show also that the regulation of PEPCK by PPARs is cell-specific and isotype-specific since rosiglitazone induces PEPCK gene expression selectively in adipocytes, and PPARα- and PPARβ-specific activators are inefficient. Hence, TZDs could lower plasma NEFAs via PPARγ and PEPCK by enhancing adipocyte glyceroneogenesis.

Original languageEnglish
Pages (from-to)933-943
Number of pages11
JournalBiochimie
Volume83
Issue number10
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Adipose tissue
  • Glyceroneogenesis
  • Hepatoma
  • Peroxisome proliferator activated receptors
  • Type 2 diabetes

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