Gavito, Ana LuisaBautista, DoloresSuarez, JuanBadran, SamirArco, RocíoPavón, Francisco JavierSerrano, AntoniaRivera, PatriciaDecara, JuanCuesta, Antonio LuisRodríguez-de-Fonseca, FernandoBaixeras, Elena2016-09-072016-09-072016-06-22Gavito AL, Bautista D, Suarez J, Badran S, Arco R, Pavón FJ, et al. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice. PLoS ONE. 2016; 11(6):e0157956http://hdl.handle.net/10668/2399Journal Article;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.enAnimalesAlimentación rica en grasaHígado grasoGlucosaHumanosInterleucina-6LeptinaMetabolismo lipídicoLípidosLipogénesisRatonesRatones consanguíneos C57BLRatones obesosObesidadRatasRatas ZuckerReceptores de interleucina-6Factor de necrosis tumoral alfaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Diet, High-FatMedical Subject Headings::Diseases::Digestive System Diseases::Liver Diseases::Fatty LiverMedical Subject Headings::Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::GlucoseMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intercellular Signaling Peptides and Proteins::CytokinesMedical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Adipokines::LeptinMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Lipid MetabolismMedical Subject Headings::Chemicals and Drugs::LipidsMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Lipid Metabolism::LipogenesisMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, ObeseMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Overweight::ObesityMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::RatsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Mutant Strains::Rats, ZuckerMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Cytokine::Receptors, Interleukin::Receptors, Interleukin-6Medical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Tumor Necrosis Factors::Tumor Necrosis Factor-alpharesearch article27333268open access10.1371/journal.pone.01579561932-6203PMC4917096