Attenuation of inflammation and cellular stress-related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knockout mice on a high-fat diet.
The development of insulin resistance in the obese is associated with chronic, low-grade inflammation. We aimed to identify novel links between obesity, insulin resistance and the inflammatory response by comparing C57BL/6 with type I interleukin-1 receptor knockout (IL-1RI(-/-)) mice, which are protected against diet-induced insulin resistance. Mice were fed a high-fat diet for 16 wk. Insulin sensitivity was measured and proteomic analysis was performed on adipose, hepatic and skeletal muscle tissues. Despite an equal weight gain, IL-1RI(-/-) mice had lower plasma glucose, insulin and triacylglycerol concentrations, compared with controls, following dietary treatment. The higher insulin sensitivity in IL-1RI(-/-) mice was associated with down-regulation of antioxidant proteins and proteasomes in adipose tissue and hepatic soluble epoxide hydrolase, consistent with a compromised inflammatory response as well as increased glycolysis and decreased fatty acid beta-oxidation in their muscle. Their lower hepatic triacylglycerol concentrations may reflect decreased flux of free fatty acids to the liver, decreased hepatic fatty acid-binding protein expression and decreased lipogenesis. Correlation analysis revealed down-regulation of classical biomarkers of ER stress in their adipose tissue, suggesting that disruption of the IL-1RI-mediated inflammatory response may attenuate cellular stress, which was associated with significant protection from diet-induced insulin resistance, independent of obesity.
de Roos
Baukje
B
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK. b.deroos@abdn.ac.uk
Rungapamestry
Vanessa
V
Ross
Karen
K
Rucklidge
Garry
G
Reid
Martin
M
Duncan
Gary
G
Horgan
Graham
G
Toomey
Sinead
S
Browne
John
J
Loscher
Christine E
CE
Mills
Kingston H G
KH
Roche
Helen M
HM
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D004822:Epididymis / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D000070780:Perilipin-2; D025341:Principal Component Analysis; D020543:Proteome; D040901:Proteomics / Q000379:methods*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008565:Membrane Proteins; D000070780:Perilipin-2; D020543:Proteome; D017472:Receptors, Interleukin-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004851:Epoxide Hydrolases