title: Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice.
abstract: Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Vida
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Gavito
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Anatomía Patológica, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Bautista
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suarez
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Arrabal
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero-Cuevas
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain fernando.rodriguez@ibima.eu elena.baixeras@ibima.eu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Laboratorio de Investigación, IBIMA/Universidad 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) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain fernando.rodriguez@ibima.eu elena.baixeras@ibima.eu.
authors.forename: Elena
authors.initials: E
authors.lastname: Baixeras
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000172:deficiency* / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D002334:Carnitine O-Palmitoyltransferase; D054890:Fatty Acid Synthase, Type I; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
keywords: Interleukin-6; Lipogenesis; Liver; Steatosis