Regulation of cytosolic phosphoenolpyruvate carboxykinase gene expression in adipocytes.

Cytosolic phosphoenolpyruvate carboxykinase (EC 4.1.1.32; PEPCK-C) catalyzes the critical regulated step in adipocyte glyceroneogenesis. Numerous studies have shown that hormones and nutrients regulate PEPCK-C at the transcriptional level. We identified two upstream cis-acting DNA elements, gAF1/PCK1 and PCK2, that control adipocyte specific transcription of the PEPCK-C gene (Pck1). Both elements are direct repeat hexanucleotides separated by 1 bp (DR1 elements; variations of the sequence AGGTCAnAGGTCA). PCK2 is located 1 kbp upstream and is the essential element of an adipocyte specific enhancer. It is a peroxisome proliferator activated receptor gamma response element (PPRE) and directs the activation of the PEPCK-C gene during adipogenesis. In addition, it is a thiazolidinedione response element in mature adipocytes. In contrast, gAF1/PCK1, centered 445 bp upstream, is a pleiotropic element that mediates tissue specific glucocorticoid action-repression in adipocytes and induction in hepatocytes. It is a negative response element for PPARgamma, RXRalpha, COUP-TFII, and several unidentified proteins in some cell types, and a positive element for COUP-TFI and HNF4 in other cells type. The purpose of this presentation is to review the discovery and characterization of these two elements in adipocytes and describe how our work has contributed to understanding the mechanisms that control adipocyte glyceroneogenesis.