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

R. Stienstra, J.A. van Diepen, C.J. Tack, M.H. Zaki, F.L. van de Veerdonk, D. Perera, G.A. Neale, G.J.E.J. Hooiveld, A. Hijmans, I. Vroegrijk, S. Berg, J. Romijn, P.C.N. Rensen, L.A.B. Joosten, M.G. Netea, T.D. Kanneganti

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406 Citations (Scopus)

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-1 beta and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were 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, and macrophage infiltration in adipose tissue were 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
Pages (from-to)15324-15329
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number37
DOIs
Publication statusPublished - 2011

Keywords

  • adipose-tissue
  • mice deficient
  • caspase-1
  • interleukin-18
  • expression
  • sensitivity
  • activation
  • il-1-beta
  • apoptosis
  • crystals

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  • Datasets

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

    Stienstra, R. (Creator), van Diepen, J. A. (Creator), Tack, C. J. (Creator), Zaki, M. H. (Creator), van de Veerdonk, F. L. (Creator), Perera, D. (Creator), Neal, G. (Creator), Hijmans, A. (Creator), Vroegrijk, I. O. (Creator), van den Berg, S. A. (Creator), Romijn, J. A. (Creator), Rensen, P. C. (Creator), Joosten, L. A. (Creator), Netea, M. G. (Creator) & Kanneganti, T. D. (Creator), Wageningen University, 21 Aug 2011

    Dataset

    Cite this

    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. E. J., Hijmans, A., Vroegrijk, I., 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