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

Stienstra, Rinke, Joosten, Leo A B, Koenen, Tim, van Tits, Berry, van Diepen, Janna A, van den Berg, Sjoerd A A, Rensen, Patrick C N, Voshol, Peter J, Fantuzzi, Giamilla, Hijmans, Anneke, Kersten, Sander, Müller, Michael, van den Berg, Wim B, van Rooijen, Nico, Wabitsch, Martin, Kullberg, Bart-Jan, van der Meer, Jos W M, Kanneganti, Thirumala, Tack, Cees J and Netea, Mihai G (2010) The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metabolism, 12 (6). pp. 593-605. ISSN 1550-4131

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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-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.

Item Type: Article
Additional Information: Copyright © 2010 Elsevier Inc. All rights reserved.
Uncontrolled 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
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 20:46
Last Modified: 14 Sep 2020 07:03
URI: https://ueaeprints.uea.ac.uk/id/eprint/47673
DOI: 10.1016/j.cmet.2010.11.011

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