Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome

Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signalling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates non-degradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-?B/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF-receptor-1. Here we show that mice lacking HOIP, LUBAC's catalytic subunit, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-?B activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. Importantly, HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a critical role for Lin-Ub in protecting against obesity-related metabolic syndrome by mitigating cell death-driven adipose tissue inflammation Overall design: Bulk RNAseq extration from Gwat of male mice, 22-24 weeks old mice Hoip fl/fl AdipoQ.Cre+(HoipA-KO) or Hoip fl/fl AdipoQ.Cre- (WT control) fed for 16 weeks with 14% Control Diet (CD) or 60% High fatdiet (HFD)

肥胖过程中发生的脂肪细胞肥大可触发慢性炎症，进而引发代谢紊乱。然而，脂肪细胞特异性炎症信号通路在代谢综合征中的作用仍不明确。线性泛素链组装复合体（linear ubiquitin chain assembly complex, LUBAC）是一类E3泛素连接酶（E3-ligase），可介导非降解型线性泛素化（Lin-Ub）。LUBAC可调控核因子κB（NF-κB）/丝裂原活化蛋白激酶（MAPK）介导的炎症反应，并可阻断肿瘤坏死因子受体1（TNF-receptor-1）等免疫受体触发的细胞死亡。本研究显示，脂肪细胞中缺失LUBAC的催化亚基HOIP的小鼠（HoipA-KO）会出现脂肪营养不良，并对肥胖诱导的代谢综合征易感性显著升高，尤其是代谢功能障碍相关性脂肪性肝病（Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD）。从机制层面来看，HOIP缺失会削弱肿瘤坏死因子（TNF）诱导的核因子κB活化，并促进人脂肪细胞发生细胞死亡。抑制半胱天冬酶8（caspase-8）介导的细胞死亡，即可阻止肥胖型HoipA-KO小鼠出现脂肪营养不良与MASLD。值得注意的是，肥胖个体脂肪组织中HOIP的表达水平与代谢健康状况呈正相关。综上，本研究结果揭示了Lin-Ub通过缓解细胞死亡介导的脂肪组织炎症，进而抵御肥胖相关代谢综合征的关键作用。实验设计：对22~24周龄雄性小鼠的附睾白色脂肪组织（Gwat）进行批量RNA测序（bulk RNAseq）样本提取；实验小鼠分为Hoip fl/fl AdipoQ.Cre+（HoipA-KO）组与Hoip fl/fl AdipoQ.Cre-（野生型对照，WT control）组，分别喂食14%热量的对照饲料（Control Diet, CD）或60%热量的高脂饲料（High-fat Diet, HFD），喂食周期为16周。