title: Pyroglutamylated RF-amide peptide (QRFP) gene is regulated by metabolic endotoxemia.
abstract: Pyroglutamylated RF-amide peptide (QRFP) is involved in the regulation of food intake, thermogenesis, adipogenesis, and lipolysis. The expression of QRFP in adipose tissue is reduced in diet-induced obesity, a mouse model in which plasma concentrations of endotoxins are slightly elevated. The present study investigated the role of metabolic endotoxemia (ME) on QRFP gene regulation. Our results uncovered the expression of QRFP in murine macrophages and cell lines. This expression has been found to be decreased in mice with ME. Low doses of lipopolysaccharide (LPS) transiently down-regulated QRFP by 59% in RAW264.7 macrophages but not in 3T3-L1 adipocytes. The effect of LPS on QRFP expression in macrophages was dependent on the inhibitor of kB kinase and TIR-domain-containing adapter-inducing interferon (IFN)-β (TRIF) but not myeloid differentiation primary response gene 88. IFN-β was induced by ME in macrophages. IFN-β sustainably reduced QRFP expression in macrophages (64%) and adipocytes (49%). IFN-γ down-regulated QRFP (74%) in macrophages only. Both IFNs inhibited QRFP secretion from macrophages. LPS-stimulated macrophage-conditioned medium reduced QRFP expression in adipocytes, an effect blocked by IFN-β neutralizing antibody. The effect of IFN-β on QRFP expression was dependent on phosphoinositide 3-kinase, p38 MAPK, and histone deacetylases. The effect of IFN-γ was dependent on MAPK/ERK kinase 1/2 and histone deacetylases. Macrophage-conditioned medium containing increased amounts of QRFP preserved adipogenesis in adipocytes. In conclusion, LPS induces IFN-β release from macrophages, which reduces QRFP expression in both macrophages and adipocytes in an autocrine/paracrine-dependent manner, suggesting QRFP as a potential biomarker in ME.
authors.affiliation: Faculty of Pharmacy (C.J., M.M., S.M., M.J.S., H.O.), Université de Montréal C.P. 6128, Succursale Centre-Ville, Québec, Canada, H3C 3J7; and Laboratory of Molecular and Cellular Endocrinology (R.G., D.G., E.G.), Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Jossart
authors.forename: Mukandila
authors.initials: M
authors.lastname: Mulumba
authors.forename: Riccarda
authors.initials: R
authors.lastname: Granata
authors.forename: Davide
authors.initials: D
authors.lastname: Gallo
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marleau
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Servant
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D017077:Culture Media, Conditioned; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D007372:Interferons / Q000502:physiology; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; C476583:Qrfpr protein, mouse; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons