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

Research output: Contribution to journalArticle

353 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-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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Inflammasomes
Insulin Resistance
Obesity
Chemokine CCL2
Adipose Tissue
Macrophages
Cytokines
Resistin
Caspase 1
Interleukin-18
High Fat Diet
Caspases
Leptin
Interleukin-1
Adipocytes
Energy Metabolism
Triglycerides
Apoptosis
Inflammation
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Inflammasome is a central player in the induction of obesity and insulin resistance. / Stienstra, Rinke; Van Diepen, Janna A.; Tack, Cees J.; Zaki, Md Hasan; Van De Veerdonk, Frank L.; Perera, Deshani; Neale, Geoffrey A.; Hooiveld, Guido J.; Hijmans, Anneke; Vroegrijk, Irene; Van Den Berg, Sjoerd; Romijn, Johannes; Rensen, Patrick C N; Joosten, Leo A B; Netea, Mihai G.; Kanneganti, Thirumala Devi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 37, 13.09.2011, p. 15324-15329.

Research output: Contribution to journalArticle

Stienstra, R, Van Diepen, JA, Tack, CJ, Zaki, MH, Van De Veerdonk, FL, Perera, D, Neale, GA, Hooiveld, GJ, Hijmans, A, Vroegrijk, I, Van Den Berg, S, Romijn, J, Rensen, PCN, Joosten, LAB, Netea, MG & Kanneganti, TD 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, vol. 108, no. 37, pp. 15324-15329. https://doi.org/10.1073/pnas.1100255108
Stienstra, Rinke ; Van Diepen, Janna A. ; Tack, Cees J. ; Zaki, Md Hasan ; Van De Veerdonk, Frank L. ; Perera, Deshani ; Neale, Geoffrey A. ; Hooiveld, Guido J. ; Hijmans, Anneke ; Vroegrijk, Irene ; Van Den Berg, Sjoerd ; Romijn, Johannes ; Rensen, Patrick C N ; Joosten, Leo A B ; Netea, Mihai G. ; Kanneganti, Thirumala Devi. / Inflammasome is a central player in the induction of obesity and insulin resistance. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 37. pp. 15324-15329.
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