The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity

Rinke Stienstra, Leo A B Joosten, Tim Koenen, Berry van Tits, Janna A van Diepen, Sjoerd A A van den Berg, Patrick C N Rensen, Peter J Voshol, Giamilla Fantuzzi, Anneke Hijmans, Sander Kersten, Michael Müller, Wim B van den Berg, Nico van Rooijen, Martin Wabitsch, Bart-Jan Kullberg, Jos W M van der Meer, Thirumala Kanneganti, Cees J Tack, Mihai G Netea

Research output: Contribution to journalArticle

438 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)593-605
Number of pages13
JournalCell Metabolism
Volume12
Issue number6
DOIs
Publication statusPublished - 1 Dec 2010

Keywords

  • Adipocytes
  • Animals
  • Calorimetry, Indirect
  • Carrier Proteins
  • Caspase 1
  • Cell Differentiation
  • Enzyme Activation
  • Histological Techniques
  • Immunoblotting
  • Inflammasomes
  • Insulin Resistance
  • Interleukin-18
  • Interleukin-1beta
  • Mice
  • Mice, Knockout
  • Obesity
  • Polymerase Chain Reaction

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