Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance.
OBJECTIVE
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
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.
Matthews
V B
VB
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, 3008, VIC, Australia.
Allen
T L
TL
Risis
S
S
Chan
M H S
MH
Henstridge
D C
DC
Watson
N
N
Zaffino
L A
LA
Babb
J R
JR
Boon
J
J
Meikle
P J
PJ
Jowett
J B
JB
Watt
M J
MJ
Jansson
J-O
JO
Bruce
C R
CR
Febbraio
M A
MA
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000235:genetics; D000818:Animals; D001823:Body Composition / Q000235:genetics; D002153:Calorimetry, Indirect; D048429:Cell Size; D004075:Diglycerides / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004075:Diglycerides; D015850:Interleukin-6; D014280:Triglycerides