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.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Carnitine O-Palmitoyltransferase / genetics
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Carnitine O-Palmitoyltransferase / metabolism
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Cytokine Receptor gp130 / metabolism
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Diet, High-Fat / adverse effects*
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Down-Regulation / drug effects
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Fatty Acids / metabolism
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Fatty Liver / blood
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Fatty Liver / genetics
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Fatty Liver / pathology*
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Interleukin-6 / administration & dosage*
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Interleukin-6 / adverse effects*
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Interleukin-6 / pharmacology
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Leptin / blood*
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Liver / enzymology
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Liver / metabolism*
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Liver / pathology
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Male
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Mice, Inbred C57BL
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Mice, Obese
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Models, Biological
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PPAR alpha / metabolism
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Rats, Zucker
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Receptors, Leptin / metabolism
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / pharmacology
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Suppressor of Cytokine Signaling 3 Protein / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
Substances
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Blood Glucose
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Fatty Acids
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Interleukin-6
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Leptin
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PPAR alpha
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Receptors, Leptin
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Recombinant Proteins
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Tumor Necrosis Factor-alpha
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Cytokine Receptor gp130
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Carnitine O-Palmitoyltransferase
Grants and funding
The present study was financially supported through funding from the Instituto de Salud Carlos III, Red de Trastornos Adictivos UE-FEDER 2012 (RD12/0028/0001); Ministerio de Economía y Competitividad(PI13/02261); Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional sobre Drogas 049/2009 and 049/2013; Consejería de Economía, Innovación y Ciencia, Junta de Andalucía(CTS-433); Consejería de Salud y Bienestar Social, Junta Andalucía (PI0552, PI0228-2013 and PI0823-2012). Samir Badran received an Erasmus+ mobility grant EU funds (code ID:DK ESBEJRG19). Juan Suarez, Antonia Serrano and F. Javier Pavón received a "MiguelServet" research contract and grant from the National System of Health, Instituto de Salud Carlos III, (grants number CP12/03109, CP14/00212, CP14/00173, respectively). Elena Baixeras received an I3SNS contract from Program of the Instituto de Salud Carlos III and Andalusian "Progreso y Salud" Foundation, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.