Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.
OBJECTIVE
The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents.


METHODS
We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents.


RESULTS
We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn ( -/- )animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn ( -/- ) animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5 days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake.


CONCLUSIONS
The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistance.
Somm
E
E
Endocrine Unit, Department of Internal Medicine, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.
Cettour-Rose
P
P
Asensio
C
C
Charollais
A
A
Klein
M
M
Theander-Carrillo
C
C
Juge-Aubry
C E
CE
Dayer
J-M
JM
Nicklin
M J H
MJ
Meda
P
P
Rohner-Jeanrenaud
F
F
Meier
C A
CA
D000273:Adipose Tissue / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000009:adverse effects*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D053574:Receptors, Interleukin-1 Type II; D012795:Sialoglycoproteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
D001786:Blood Glucose; D004041:Dietary Fats; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D012795:Sialoglycoproteins