School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Diabetes. 2022 Dec 1;71(12):2557-2571. doi: 10.2337/db21-1099.
The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.
肥胖症期间脂肪组织巨噬细胞（ATMs）的表型和功能可塑性在调节脂肪和全身炎症中起着关键作用。张力反应增强子结合蛋白（TonEBP）（也称为 NFAT5）是一种应激蛋白，介导细胞对多种代谢损伤的反应。在这里，我们表明，髓样细胞特异性 TonEBP 耗竭可减少高脂肪饮食诱导肥胖小鼠的炎症和胰岛素抵抗，但不影响肥胖程度。这种表型与代谢激活的巨噬细胞的积累减少和促炎表型减少、与胰岛素抵抗相关的炎症因子表达降低以及胰岛素敏感性增强有关。TonEBP 在肥胖小鼠的 ATMs 中表达上调，Sp1 被鉴定为 TonEBP 诱导的核心调节剂。在肥胖模拟条件下，巨噬细胞中 TonEBP 的耗竭减少了与胰岛素抵抗相关基因的诱导，促进了与胰岛素敏感性相关基因的诱导，从而改善了脂肪细胞中的胰岛素信号和葡萄糖摄取。外周血单核细胞中 TonEBP 的 mRNA 表达与小鼠和人类的血糖水平呈正相关。这些发现表明巨噬细胞中的 TonEBP 促进肥胖相关的全身胰岛素抵抗和炎症，下调 TonEBP 可能在肥胖期间诱导健康的代谢状态。
