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

• Published in: Endocrinology (Philadelphia) Vol. 148; no. 8; pp. 4007 - 4014
• Main Authors: Khazen, Wael, Distel, Emilie, Collinet, Martine, Chaves, Valéria E, M’Bika, Jean-Pierre, Chany, Charles, Achour, Ammar, Benelli, Chantal, Forest, Claude
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.08.2007
• Subjects: 3T3 Cells; Adipocytes - drug effects; Adipocytes - enzymology; Adipocytes - immunology; Adult; Animals; Biological and medical sciences; Carbon Radioisotopes; Cytosol - enzymology; Fatty Acids - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - immunology; Glycerol - metabolism; Humans; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Lipid Metabolism - drug effects; Lipid Metabolism - immunology; Male; Mice; Mice, Inbred BALB C; Paracrine Communication - drug effects; Paracrine Communication - immunology; Phosphoenolpyruvate Carboxykinase (GTP) - genetics; Phosphoenolpyruvate Carboxykinase (GTP) - metabolism; Pyruvic Acid; Vertebrates: endocrinology; Adipocyte; Carbon-carbon lyases; Enzyme; Carboxy-lyases; Acute; Lyases; Inhibition; Phosphoenolpyruvate carboxykinase (ATP); Gamma interferon
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-1760

Interferon γ (IFN-γ) 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-γ targets. We injected mice with IFN-γ, and exposed either AT explants and isolated adipocytes from humans and mice or 3T3-F442A adipocytes to IFN-γ before monitoring expression of genes involved in lipid metabolism and the metabolic consequences. We show that IFN-γ 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-γ, while that of PEPCK-C was rapidly and drastically lowered. IFN-γ effect opposed that of the β-agonist isoproterenol and of 8-Br-cAMP. In IFN-γ-treated mice, PEPCK-C gene expression was decreased in AT, but not in liver or kidney. Thus, IFN-γ 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.