Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance |
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Authors: | V B Matthews T L Allen S Risis M H S Chan D C Henstridge N Watson L A Zaffino J R Babb J Boon P J Meikle J B Jowett M J Watt J-O Jansson C R Bruce M A Febbraio |
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Institution: | 1. Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, PO Box?6492, St Kilda Road Central, Melbourne, 3008, VIC, Australia 2. Department of Physiology, Monash University, Clayton, VIC, Australia 3. Institute of Neuroscience and Physiology/Endocrinology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Abstract: | Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 ?/?) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 ?/? and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 ?/? mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 ?/? and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 ?/? mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 ?/? relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism. |
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