The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity.
Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1β and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1β and IL-18 requires cleavage by caspase-1, a cysteine protease regulated by a protein complex called the inflammasome. We demonstrate that the inflammasome/caspase-1 governs adipocyte differentiation and insulin sensitivity. Caspase-1 is upregulated during adipocyte differentiation and directs adipocytes toward a more insulin-resistant phenotype. Treatment of differentiating adipocytes with recombinant IL-1β and IL-18, or blocking their effects by inhibitors, reveals that the effects of caspase-1 on adipocyte differentiation are largely conveyed by IL-1β. Caspase-1 and IL-1β activity in adipose tissue is increased both in diet-induced and genetically induced obese animal models. Conversely, mice deficient in caspase-1 are more insulin sensitive as compared to wild-type animals. In addition, differentiation of preadipocytes isolated from caspase-1(-/-) or NLRP3(-/-) mice resulted in more metabolically active fat cells. In vivo, treatment of obese mice with a caspase-1 inhibitor significantly increases their insulin sensitivity. Indirect calorimetry analysis revealed higher fat oxidation rates in caspase-1(-/-) animals. In conclusion, the inflammasome is an important regulator of adipocyte function and insulin sensitivity, and caspase-1 inhibition may represent a novel therapeutic target in clinical conditions associated with obesity and insulin resistance.
Department of Medicine, Radboud University Nijmegen Medical Centre and Nijmegen Institute for Infection, Inflammation and Immunity (N4I), Nijmegen 6525 GA, The Netherlands. r.stienstra@aig.umcn.nl
Rinke
R
Stienstra
Leo A B
LA
Joosten
Tim
T
Koenen
Berry
B
van Tits
Janna A
JA
van Diepen
Sjoerd A A
SA
van den Berg
Patrick C N
PC
Rensen
Peter J
PJ
Voshol
Giamilla
G
Fantuzzi
Anneke
A
Hijmans
Sander
S
Kersten
Michael
M
Müller
Wim B
WB
van den Berg
Nico
N
van Rooijen
Martin
M
Wabitsch
Bart-Jan
BJ
Kullberg
Jos W M
JW
van der Meer
Thirumala
T
Kanneganti
Cees J
CJ
Tack
Mihai G
MG
Netea
D017667:Adipocytes / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002153:Calorimetry, Indirect; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006652:Histological Techniques; D015151:Immunoblotting; D058847:Inflammasomes / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000378:metabolism*; D016133:Polymerase Chain Reaction
D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1