Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis

Chen et al. show that the endoplasmic reticulum stress sensor IRE1 alpha acts in white and beige adipocytes to restrain beige adipocyte activation, through regulation of lipolysis and Pgc1 alpha messenger RNA levels, respectively. Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1 alpha (IRE1 alpha), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1 alpha promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or beta 3-adrenergic stimulation. Loss of IRE1 alpha alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic beta 3-adrenergic stimulation. Notably, IRE1 alpha suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1 alpha bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.

Automated summary

Chen et al. discovered that the IRE1 alpha endoplasmic reticulum stress sensor inhibits beige adipocyte activation in white and beige adipocytes by regulating lipolysis and Pgc1 alpha messenger RNA levels. The research shows the therapeutic potential of blocking IRE1 alpha in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.