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

journal contribution
posted on 2023-05-20, 04:41 authored by Matthews, VB, Allen, TL, Risis, S, Chan, MHS, Darren HenstridgeDarren Henstridge, Watson, N, Zaffino, LA, Babb, JR, Boon, J, Meikle, PJ, Jowett, JB, Watt, MJ, Jansson, J-O, Bruce, CR, Febbraio, MA

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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Clinical health not elsewhere classified