Gadd45b的脂肪细胞特异性消融通过Fgf1b启动子高甲基化加剧了肥胖相关的细胞衰老和代谢紊乱
Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.
摘要(中文译文)
细胞衰老参与肥胖相关脂肪功能障碍，但该过程的上游调控因子仍知之甚少。在此，我们鉴定生长停滞与DNA损伤诱导蛋白45β（Gadd45b）作为脂肪细胞衰老及全身代谢稳态的适应性调控因子。在肥胖人类受试者的脂肪组织中GADD45B表达升高，并与衰老相关标志物呈正相关。小鼠脂肪细胞特异性Gadd45b缺失在高脂饮食下引起脂肪库选择性重塑，表现为腹股沟脂肪肥大但附睾白色脂肪组织（eWAT）萎缩，并伴有DNA损伤增强和显著的衰老。这些改变进而导致脂解反应受损、肝脂肪变性和胰岛素抵抗，凸显了Gadd45b在营养过载期间维持eWAT可扩展性中的关键作用。机制上，Gadd45b缺陷导致eWAT中成纤维细胞生长因子1b（Fgf1b）启动子高甲基化及Fgf1表达降低，从而加剧脂肪衰老和代谢异常，而重组FGF1治疗可部分逆转这些缺陷。总之，我们的研究结果确立Gadd45b作为一种脂肪库特异性表观遗传调控因子，维持脂肪组织可塑性，并将DNA损伤应答与肥胖中的脂肪细胞衰老及代谢稳态联系起来。
Abstract
Cellular senescence contributes to obesity-associated adipose dysfunction, yet the upstream regulators of this process remain poorly understood. Here, we identified growth arrest and DNA damage-inducible protein 45 beta (Gadd45b) as an adaptive regulator of adipocyte senescence and systemic metabolic homeostasis. GADD45B expression was elevated in adipose tissue from obese human subjects and positively correlated with senescence-related markers. Adipocyte-specific Gadd45b deletion in mice caused depot-selective remodeling under high-fat diet, with inguinal fat hypertrophy but epididymal white adipose tissue (eWAT) atrophy, accompanied by enhanced DNA damage and pronounced senescence. These alterations thereby contributed to impaired lipolytic response, hepatic steatosis and insulin resistance, underscoring the vital role of Gadd45b in maintaining eWAT expandability during nutritional overload. Mechanistically, Gadd45b deficiency led to hypermethylation of fibroblast growth factor 1b (Fgf1b) promoter and reduced Fgf1 expression in eWAT, thereby exacerbating adipose senescence and metabolic abnormalities, while recombinant FGF1 treatment partially reversed these defects. Collectively, our findings establish Gadd45b as a depot-specific epigenetic regulator that sustains adipose tissue plasticity and links DNA damage responses to adipocyte senescence and metabolic homeostasis in obesity.
如何引用
AMA
Fan Hu, Yafen Ye, Ningning Bai, Jun Xu, Yikai Wang, Yingying Su, et al. Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.. Cell death and differentiation. 2026; doi:10.1038/s41418-026-01784-9.
APA
Fan Hu, Yafen Ye, Ningning Bai, Jun Xu, Yikai Wang, Yingying Su, et al (2026). Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.. Cell death and differentiation. https://doi.org/10.1038/s41418-026-01784-9
GB/T 7714
Fan Hu, Yafen Ye, Ningning Bai, Jun Xu, Yikai Wang, Yingying Su, et al. Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.[J]. Cell death and differentiation, 2026 doi:10.1038/s41418-026-01784-9.
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