title: Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice.
abstract: High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats.
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Gavito
authors.affiliation: Unidad de Gestión Clínica de Anatomía Patológica, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Bautista
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suarez
authors.affiliation: University College South Denmark, 6705, Esbjerg, Denmark.
authors.forename: Samir
authors.initials: S
authors.lastname: Badran
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Arco
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Danish Diabetes Academy, Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Antonio Luis
authors.initials: AL
authors.lastname: Cuesta
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-de-Fonseca
authors.affiliation: Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.|Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga Spain.
authors.forename: Elena
authors.identifier: http://orcid.org/0000-0001-6955-2434
authors.initials: E
authors.lastname: Baixeras
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000473:pathology*; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D020738:Leptin / Q000097:blood*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D047493:PPAR alpha / Q000378:metabolism; D011924:Rats, Zucker; D054411:Receptors, Leptin / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D015850:Interleukin-6; D020738:Leptin; D047493:PPAR alpha; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D002334:Carnitine O-Palmitoyltransferase