TY - JOUR
T1 - Inflammasome is a central player in the induction of obesity and insulin resistance
AU - Stienstra, Rinke
AU - Van Diepen, Janna A.
AU - Tack, Cees J.
AU - Zaki, Md Hasan
AU - Van De Veerdonk, Frank L.
AU - Perera, Deshani
AU - Neale, Geoffrey A.
AU - Hooiveld, Guido J.
AU - Hijmans, Anneke
AU - Vroegrijk, Irene
AU - Van Den Berg, Sjoerd
AU - Romijn, Johannes
AU - Rensen, Patrick C.N.
AU - Joosten, Leo A.B.
AU - Netea, Mihai G.
AU - Kanneganti, Thirumala Devi
PY - 2011/9/13
Y1 - 2011/9/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053087484&partnerID=8YFLogxK
U2 - 10.1073/pnas.1100255108
DO - 10.1073/pnas.1100255108
M3 - Article
C2 - 21876127
AN - SCOPUS:80053087484
SN - 0027-8424
VL - 108
SP - 15324
EP - 15329
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -