The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity.
until further notice
SourceCell Metabolism, 12, 6, (2010), pp. 593-605
Article / Letter to editor
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Laboratory of Genetic, Endocrine and Metabolic Diseases
SubjectIGMD 5: Health aging / healthy living; N4i 1: Pathogenesis and modulation of inflammation; N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 1: Infection and autoimmunity
Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1beta and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1beta 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-1beta and IL-18, or blocking their effects by inhibitors, reveals that the effects of caspase-1 on adipocyte differentiation are largely conveyed by IL-1beta. Caspase-1 and IL-1beta 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.
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