• Cell metabolism · Dec 2010

    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, and Mihai G Netea.
    • 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
    • Cell Metab. 2010 Dec 1; 12 (6): 593-605.

    AbstractObesity-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.Copyright © 2010 Elsevier Inc. All rights reserved.

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