Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family.
A growing body of evidence suggests that cytokines of the interleukin-1 (IL-1) family, particularly IL-1β but also IL-1Ra and IL-18, are involved in obesity-associated inflammation. IL-1β is produced via cleavage of pro-IL-1β by caspase-1, which in turn is activated by a multiprotein complex called the inflammasome. The components of the NLRP3 inflammasome are involved in sensing obesity-associated danger signals, both in mice and in human (obese) subjects, with caspase-1 seemingly the most crucial regulator. Autophagy is upregulated in obesity and may function as a mechanism to control IL-1β gene expression in adipose tissue to mitigate chronic inflammation. All these mechanisms are operative in human adipose tissue and appear to be more pronounced in human visceral compared to subcutaneous tissue. In animal studies, blocking caspase-1 activity results in decreased weight gain, decreased inflammation, and improved insulin sensitivity. Human intervention studies with IL-1Ra (anakinra) have reported beneficial effects in patients with diabetes, yet without significant changes in insulin sensitivity. Clearly, the IL-1 family of cytokines, especially IL-1β, plays an important role in obesity-associated inflammation and insulin resistance and may represent a therapeutic target to reverse the detrimental metabolic consequences of obesity.
Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. c.tack@aig.umcn.nl
Cees J
CJ
Tack
Rinke
R
Stienstra
Leo A B
LA
Joosten
Mihai G
MG
Netea
D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D007333:Insulin Resistance / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000276:immunology / Q000503:physiopathology*; D050151:Subcutaneous Fat / Q000378:metabolism
D002352:Carrier Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D020382:Interleukin-18; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1