Hyperglycemia Activates Caspase-1 and TXNIP-Mediated IL-1β Transcription in Human Adipose Tissue

OBJECTIVE-Obesity is characterized by elevated levels of proinflammatory cytokines, including interleukin (IL)-1 beta, that contribute to the development of insulin resistance. In this study, we set out to investigate whether hyperglycemia drives IL-1 beta production and caspase-1 activation in murine and human adipose tissue, thus inducing insulin resistance. RESEARCH DESIGN AND 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-1 beta 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-1 beta transcription (twofold, P < 0.01) and a significant increase in IL-1 beta secretion. TXNIP suppression in human adipocytes, either by a small interfering RNA approach or a peroxisome proliferator-activated receptor-gamma 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-1 beta levels. CONCLUSIONS-High glucose activates caspase-1 in human and murine adipose tissue. Glucose-induced activation of TXNIP mediates IL-1 beta mRNA expression levels and intracellular pro-IL-1 beta accumulation in adipose tissue. The concerted actions lead to enhanced secretion of IL-1 beta in adipose tissue that may contribute to the development of insulin resistance. Diabetes 60:517-524, 2011