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 Voshol, Giamilla Fantuzzi, Anneke Hijmans, Sander Kersten, Michael Müller, W. 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. 2010. The Inflammasome-Mediated Caspase-1 Activation Controls Adipocyte Differentiation and Insulin Sensitivity. Cell Metabolism. December 1. 12
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Abstract / summary in English:

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.

Keywords in English: cysteine protease caspase-1, proinflammatory cytokines, IL-1β, adipose tissue, adipogenesis, obesity, insulin-resistance, insulin sensitivity, Type 2 Diabetes, Metabolic Syndrome, Pre-diabetes