Evidence for selective induction of phosphoenolpyruvate carboxykinase gene expression by unsaturated and nonmetabolized fatty acids in adipocytes

Polyunsaturated fatty acids (PUFAs) and 3-thia fatty acids are hypolipidemic and decrease insulin resistance in Type II diabetic animals. To exert such an action, these FAs could decrease adipose tissue lipolysis or increase esterification. Glyceroneogenesis is an important metabolic pathway in adipocytes for re-esterification of FAs originating from lipolysis and in hepatocytes for triacylglycerol synthesis during fasting. Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) plays a key role in this pathway. Here we show that the PUFA docosahexaenoic acid (DHA) stimulates PEPCK mRNA in glucose-deprived adipose tissue explants from fed rats and in 3T3-F442A differentiated adipocytes. This effect is maximum at 3 h, stable up to at least 11 h of treatment, and affects the transcription of the gene. PEPCK mRNA half-life is not affected. Among a series of adipocyte transcripts, only the adipocyte lipid binding protein mRNA is also increased by DHA, although later than the PEPCK mRNA and at a much lower extent. DHA has no effect on PEPCK gene expression in the H4IIE hepatoma cells in which this gene is responsive to other inducers like cAMP. This lack of effect is not due to a failure of DHA to act in H4IIE cells since it induces the carnitine palmitoyltransferase I (CPT-1) mRNA. Therefore, the DHA effect appears to be cell-selective. Results of experiments using either tetradecylthio acetic acid and a-bromopalmitate, two nonmetabolized FAs, or a series of inhibitors of FA metabolism show that the FA effect on PEPCK mRNA is not due to a product of its metabolism. Hence, polyunsaturated and nonmetabolized FAs stimulate adipose PEPCK, therefore potentially enhancing glyceroneogenesis and reducing FA output. This mechanism could participate in the hypolipidemic action of PUFAs.