IL-33 and ST2 license beige and brown adipocytes for uncoupled respiration

For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the 'alarmin' IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein, and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. mRNA profiles of brown adipose tissues and inguinal white adipose tissues from postnatal day 0.5 and 24, respectively, WT and IL-33 knockout mice.针对有胎盘哺乳动物而言，从子宫内母体环境向出生后生命阶段的过渡，需要激活产热过程以维持核心体温。该过程主要通过诱导棕色与米色脂肪细胞中的解偶联蛋白1（uncoupling protein 1, UCP1）完成，而棕色及米色脂肪细胞正是解偶联呼吸的主要位点。尽管该过程至关重要，但有胎盘哺乳动物如何授权其产热脂肪细胞参与出生后解偶联呼吸，目前仍不明晰。本研究证实，警报素IL-33——一种可激活2型免疫应答的核细胞因子——可授权棕色与米色脂肪细胞进行解偶联呼吸。研究发现，在缺失IL-33或ST2的情况下，米色与棕色脂肪细胞可正常发育，但无法表达Ucp1 mRNA的正确剪接体，进而导致UCP1蛋白缺失，解偶联呼吸与体温调节功能受损。综上，上述数据表明IL-33与ST2可作为发育开关，在围产期授权产热过程。本研究的数据集包含野生型（wild type, WT）与IL-33敲除小鼠的mRNA表达谱，样本分别为出生后0.5天的棕色脂肪组织，以及出生后24天的腹股沟白色脂肪组织。