Acute and selective inhibition of adipocyte glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase by interferon gamma.
Interferon gamma (IFN-gamma) 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-gamma targets. We injected mice with IFN-gamma, and exposed either AT explants and isolated adipocytes from humans and mice or 3T3-F442A adipocytes to IFN-gamma before monitoring expression of genes involved in lipid metabolism and the metabolic consequences. We show that IFN-gamma induces a large increase in FA release without affecting glycerol output and decreases [1-(14)C]-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-gamma, while that of PEPCK-C was rapidly and drastically lowered. IFN-gamma effect opposed that of the beta-agonist isoproterenol and of 8-Br-cAMP. In IFN-gamma-treated mice, PEPCK-C gene expression was decreased in AT, but not in liver or kidney. Thus, IFN-gamma 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.
Khazen
Wael
W
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.
Distel
Emilie
E
Collinet
Martine
M
Chaves
Valéria E
VE
M'Bika
Jean-Pierre
JP
Chany
Charles
C
Achour
Ammar
A
Benelli
Chantal
C
Forest
Claude
C
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D000328:Adult; D000818:Animals; D002250:Carbon Radioisotopes; D003600:Cytosol / Q000201:enzymology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D005990:Glycerol / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019899:Paracrine Communication / Q000187:drug effects / Q000276:immunology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid
D002250:Carbon Radioisotopes; D005227:Fatty Acids; D007371:Interferon-gamma; D019289:Pyruvic Acid; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005990:Glycerol