Glucocorticoids repress induction by thiazolidinediones, fibrates, and fatty acids of phosphoenolpyruvate carboxykinase gene expression in adipocytes

✍ Scribed by Martine Glorian; Sylvie Franckhauser-Vogel; Danielle Robin; Pierre Robin; Claude Forest

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 255 KB
• Volume: 68
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/(sici)1097-4644(19980301)68:3<298::aid-jcb2>3.0.co;2-p

✦ Synopsis

Phosphoenolpyruvate carboxykinase (PEPCK) exerts a glyceroneogenic function in adipocytes in which transcription of its gene is increased by unsaturated fatty acids and fibrates. We used cultured rat adipose tissue fragments and 3T3-F442A adipocytes to show that the antidiabetic thiazolidinedione BRL 49653, a ligand and an activator of the ␥ isoform of peroxisome proliferator activated receptors (PPAR␥), is a potent inducer of PEPCK mRNA. In 3T3-F442A adipocytes, the effect of BRL 49653 is rapid and concentration dependent, with a maximum reached at 1 µM and a half-maximum at 10-100 nM. PEPCK mRNA is similarly induced by the natural ligand of PPAR␥, the 15-deoxy-⌬ 12-14 prostaglandin J2. These observations strongly suggest that PPAR␥ is a primary regulator of PEPCK gene expression in adipocytes. Dexamethasone at 10 nM repress induction of PEPCK mRNA by 1 µM BRL 49653, 0.32 mM oleate, or 1 mM clofibrate, in a cycloheximide-independent manner. The antiglucocorticoid RU 38486 prevents dexamethasone action, demonstrating involvement of the glucocorticoid receptor. Stable transfectants of 3T3-F442A adipocytes bearing Ϫ2100 to ϩ69 base pairs of the PEPCK gene promoter fused to the chloramphenicol acetyltransferase (CAT) gene respond to 1 µM BRL 49653 or 1 mM clofibrate by a large increase in CAT activity, which is prevented by the simultaneous addition of 10 nM dexamethasone. Hence, in adipocytes, glucocorticoids act directly through the 5Ј-flanking region of the PEPCK gene to repress, in a dominant fashion, the stimulation of PEPCK gene transcription by thiazolidinediones and fibrates.