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RESEARCH ARTICLE
Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice
Margarita Vida, Ana Luisa Gavito, Francisco Javier Pavón, Dolores Bautista, Antonia Serrano, Juan Suarez, Sergio Arrabal, Juan Decara, Miguel Romero-Cuevas, Fernando Rodríguez de Fonseca, Elena Baixeras
Disease Models & Mechanisms 2015 8: 721-731; doi: 10.1242/dmm.019166
Margarita Vida
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Ana Luisa Gavito
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Francisco Javier Pavón
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Dolores Bautista
4Unidad de Gestión Clínica de Anatomía Patológica, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Antonia Serrano
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Juan Suarez
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Sergio Arrabal
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Juan Decara
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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Miguel Romero-Cuevas
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
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Fernando Rodríguez de Fonseca
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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  • For correspondence: fernando.rodriguez@ibima.eu elena.baixeras@ibima.eu
Elena Baixeras
1Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain
2Centro 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
3Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain
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  • For correspondence: fernando.rodriguez@ibima.eu elena.baixeras@ibima.eu
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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.

Footnotes

  • ↵* These authors contributed equally as co-first authors

  • ↵‡ These authors contributed equally as co-senior authors

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    E.B. and F.R.d.F. conceived and designed the experiments. M.V., A.L.G., F.J.P., D.B., A.S., J.S., S.A. and J.D. performed the experiments. M.R.-C., E.B. and F.J.P. analyzed the data. E.B. and F.R.d.F. wrote the paper.

  • Funding

    The present study was financially supported through funding from the Instituto de Salud Carlos III, Red de Trastornos Adictivos UE-FEDER 2012 (RD12/0028); Ministerio de Economía y Competitividad (PI13/02261); Plan Nacional sobre Drogas 049/2009 and 049/2013; Consejería de Economía, Innovación y Ciencia, Junta de Andalucía UE-FEDER (CTS-433); Consejería de Salud y Bienestar Social, Junta Andalucía (TCMR0019, PI0552, PI0228-2013 and PI0823-2012). E.B. is a tenured investigator through the I3SNS Program of the Andalusian “Progreso y Salud” Foundation, Spain. J.S. received a “Miguel Servet” research contract and grant from the National System of Health (Instituto de Salud Carlos III, grant number CP12/03109). The funders were not involved in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Supplementary material

    Supplementary material available online at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.019166/-/DC1

  • Received November 17, 2014.
  • Accepted April 17, 2015.
  • © 2015. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Interleukin-6
  • Liver
  • Lipogenesis
  • Steatosis

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RESEARCH ARTICLE
Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice
Margarita Vida, Ana Luisa Gavito, Francisco Javier Pavón, Dolores Bautista, Antonia Serrano, Juan Suarez, Sergio Arrabal, Juan Decara, Miguel Romero-Cuevas, Fernando Rodríguez de Fonseca, Elena Baixeras
Disease Models & Mechanisms 2015 8: 721-731; doi: 10.1242/dmm.019166
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RESEARCH ARTICLE
Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice
Margarita Vida, Ana Luisa Gavito, Francisco Javier Pavón, Dolores Bautista, Antonia Serrano, Juan Suarez, Sergio Arrabal, Juan Decara, Miguel Romero-Cuevas, Fernando Rodríguez de Fonseca, Elena Baixeras
Disease Models & Mechanisms 2015 8: 721-731; doi: 10.1242/dmm.019166

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