Inflammasome is a central player in the induction of obesity and insulin resistance

Rinke Stienstra, Janna A. Van Diepen, Cees J. Tack, Md Hasan Zaki, Frank L. Van De Veerdonk, Deshani Perera, Geoffrey A. Neale, Guido J. Hooiveld, Anneke Hijmans, Irene Vroegrijk, Sjoerd Van Den Berg, Johannes Romijn, Patrick C N Rensen, Leo A B Joosten, Mihai G. Netea, Thirumala Devi Kanneganti

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388 Scopus citations

Abstract

Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1were resistant to the development of high-fat diet-induced obesity,which correlated with protection from obesity-induced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, andmacrophage infiltration in adipose tissuewere all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)15324-15329
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number37
DOIs
StatePublished - Sep 13 2011

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Stienstra, R., Van Diepen, J. A., Tack, C. J., Zaki, M. H., Van De Veerdonk, F. L., Perera, D., Neale, G. A., Hooiveld, G. J., Hijmans, A., Vroegrijk, I., Van Den Berg, S., Romijn, J., Rensen, P. C. N., Joosten, L. A. B., Netea, M. G., & Kanneganti, T. D. (2011). Inflammasome is a central player in the induction of obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 108(37), 15324-15329. https://doi.org/10.1073/pnas.1100255108