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, LUBACs 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 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 fat diet (HFD)肥胖过程中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未明确。线性泛素链组装复合物（linear ubiquitin chain assembly complex, LUBAC）是一类E3泛素连接酶，能够介导非降解型线性泛素化（Lin-Ub）。LUBAC可调控NF-κB/MAPK通路驱动的炎症反应，并抑制肿瘤坏死因子受体1（TNF-receptor-1）等免疫受体触发的细胞死亡。本研究发现，在脂肪细胞中缺失LUBAC催化亚基HOIP的小鼠（HoipA-KO）会出现脂肪营养不良，且对肥胖诱导的代谢综合征，尤其是代谢功能障碍相关性脂肪性肝病（Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD）具有更高的易感性。机制层面，HOIP的缺失会削弱TNF诱导的NF-κB激活，并促进人脂肪细胞的细胞死亡。抑制半胱天冬酶-8（caspase-8）介导的细胞死亡，足以阻止HoipA-KO肥胖小鼠出现脂肪营养不良与MASLD。值得注意的是，肥胖人群脂肪组织中的HOIP表达水平与代谢健康状态呈显著正相关。综上，本研究结果揭示了线性泛素化通过缓解细胞死亡驱动的脂肪组织炎症，在抵御肥胖相关代谢综合征中发挥的关键作用。 本研究的批量RNA测序样本取自22~24周龄雄性小鼠的附睾白色脂肪组织（gonadal white adipose tissue, Gwat），受试小鼠分为Hoip fl/fl AdipoQ.Cre+（HoipA-KO）组与Hoip fl/fl AdipoQ.Cre-（野生型对照，WT control）组，分别饲喂14%能量对照饮食（Control Diet, CD）或60%能量高脂饮食（High fat diet, HFD）16周。