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Acute and Selective Inhibition of Adipocyte Glyceroneogenesis and Cytosolic Phosphoenolpyruvate Carboxykinase by Interferon

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S747 (W.K., E.D., M.C., V.E.C., C.B., C.F.) and Laboratoire des interférons et de la sarcolectine (J.-P.M., C.C., A.A.), Université Paris Descartes, Centre Universitaire des Saints-Pères, 75006 Paris, France; and Department of Physiology (V.E.C.), School of Medicine of Ribeirão Preto Avenida Bandeirantes 3900, 14.049 Ribeirão Preto, S.P. Brazil

Address all correspondence and requests for reprints to: Dr. Claude Forest, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S747, Université Paris Descartes, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France. E-mail: claude.forest{at}univ-paris5.fr.

Interferon (IFN-) was previously shown to promote fatty acid (FA) release from adipose tissue (AT). Net lipolysis is an equilibrium between triglyceride breakdown and FA re-esterification. The latter requires activated glyceroneogenesis for glycerol-3-phosphate synthesis and increased cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), the key enzyme in this pathway. We wondered whether glyceroneogenesis and PEPCK-C would be IFN- targets. We injected mice with IFN-, and exposed either AT explants and isolated adipocytes from humans and mice or 3T3-F442A adipocytes to IFN- before monitoring expression of genes involved in lipid metabolism and the metabolic consequences. We show that IFN- induces a large increase in FA release without affecting glycerol output and decreases [1-¹⁴C]-pyruvate incorporation into lipids, thus demonstrating that FA re-esterification is reduced due to diminished glyceroneogenesis. A series of mRNA encoding proteins involved in FA metabolism remained unaffected by IFN-, while that of PEPCK-C was rapidly and drastically lowered. IFN- effect opposed that of the ß-agonist isoproterenol and of 8-Br-cAMP. In IFN--treated mice, PEPCK-C gene expression was decreased in AT, but not in liver or kidney. Thus, IFN- exerts a tissue-specific action in rodents and humans, having glyceroneogenesis and the PEPCK-C gene as selective targets to intensify FA release from adipocytes.