title: Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue.
abstract: OBJECTIVE
  Obesity is characterized by elevated levels of proinflammatory cytokines, including interleukin (IL)-1β, that contribute to the development of insulin resistance. In this study, we set out to investigate whether hyperglycemia drives IL-1β production and caspase-1 activation in murine and human adipose tissue, thus inducing insulin resistance.
  
  
  METHODS
  ob/ob animals were used as a model to study obesity and hyperglycemia. Human adipose tissue fragments or adipocytes were cultured in medium containing normal or high glucose levels. Additionally, the role of thioredoxin interacting protein (TXNIP) in glucose-induced IL-1β production was assessed.
  
  
  RESULTS
  TXNIP and caspase-1 protein levels were more abundantly expressed in adipose tissue of hyperglycemic ob/ob animals as compared with wild-type mice. In human adipose tissue, high glucose resulted in a 10-fold upregulation of TXNIP gene expression levels (P < 0.01) and a 10% elevation of caspase-1 activity (P < 0.05), together with induction of IL-1β transcription (twofold, P < 0.01) and a significant increase in IL-1β secretion. TXNIP suppression in human adipocytes, either by a small interfering RNA approach or a peroxisome proliferator-activated receptor-γ agonist, counteracted the effects of high glucose on bioactive IL-1 production (P < 0.01) mainly through a decrease in transcription levels paralleled by reduced intracellular pro-IL-1β levels.
  
  
  CONCLUSIONS
  High glucose activates caspase-1 in human and murine adipose tissue. Glucose-induced activation of TXNIP mediates IL-1β mRNA expression levels and intracellular pro-IL-1β accumulation in adipose tissue. The concerted actions lead to enhanced secretion of IL-1β in adipose tissue that may contribute to the development of insulin resistance.
authors.affiliation: Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. t.koenen@aig.umcn.nl
authors.forename: Tim B
authors.initials: TB
authors.lastname: Koenen
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: van Tits
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; C486715:TXNIP protein, human; D020170:Caspase 1; D005947:Glucose