Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

• Published in: Diabetologia Vol. 53; no. 11; pp. 2431 - 2441
• Main Authors: Matthews, V. B, Allen, T. L, Risis, S, Chan, M. H. S, Henstridge, D. C, Watson, N, Zaffino, L. A, Babb, J. R, Boon, J, Meikle, P. J, Jowett, J. B, Watt, M. J, Jansson, J.-O, Bruce, C. R, Febbraio, M. A
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.11.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adiposity; Adiposity - genetics; Animals; Biological and medical sciences; Body Composition; Body Composition - genetics; Body fat; Calorimetry, Indirect; Cell Size; Cytokines; deficiency; Dehydrogenases; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Diglycerides; Diglycerides - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Female; Gastroenterology. Liver. Pancreas. Abdomen; genetics; Glucose; Human Physiology; immunology; Inflammation; Inflammation - genetics; Insulin Resistance; Insulin Resistance - genetics; Interleukin-6; Interleukin-6 - deficiency; Interleukin-6 - genetics; Internal Medicine; Kinases; Lipids; Liver; Liver - immunology; Liver - metabolism; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical and Health Sciences; Medical research; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Musculoskeletal system; noninsulin-dependent diabetes mellitus; Obesity; Obesity - genetics; Obesity - metabolism; Other diseases. Semiology; pathology; Physiology; Proteins; Signal transduction; Triglycerides; Triglycerides - metabolism; Type 2 diabetes; Australia; United States > US; Type 2 diabetes; Obesity; Signal transduction; Fatty liver; Cytokines; Endocrinopathy; Rodentia; Nutrition disorder; Cytokine; Metabolic diseases; Hepatic disease; Inflammation; Interleukin 6; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Digestive diseases; Insulin resistance; Nutritional status
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-010-1865-y

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.