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

R. Stienstra, L.A. Joosten, T. Koenen, B. van Tits, J.A. van Diepen, S.A.A. van den Berg, P.C. Rensen, P.J. Voshol, G. Fantuzzi, A. Hijmans, A.H. Kersten, M.R. Müller, W.B. van den Berg, N. van Rooijen, M. Wabitsch, B.J. Kullberg, J.W. van der Meer, T. Kanneganti, C.J. Tack, M.G. Netea

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Abstract

Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1ß and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1ß 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-1ß and IL-18, or blocking their effects by inhibitors, reveals that the effects of caspase-1 on adipocyte differentiation are largely conveyed by IL-1ß. Caspase-1 and IL-1ß 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
JournalCell Metabolism
Volume12
Issue number6
DOIs
Publication statusPublished - 2010

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Keywords

  • innate immunity
  • adipose-tissue
  • ppar-gamma
  • resistance
  • obesity
  • mice
  • murine
  • coactivators
  • inhibition
  • receptors

Cite this

Stienstra, R., Joosten, L. A., Koenen, T., van Tits, B., van Diepen, J. A., van den Berg, S. A. A., ... Netea, M. G. (2010). The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metabolism, 12(6), 593-605. https://doi.org/10.1016/j.cmet.2010.11.011