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SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity
Cell Metabolism ( IF 27.7 ) Pub Date : 2022-04-12 , DOI: 10.1016/j.cmet.2022.03.010
Gung Lee 1 , Ye Young Kim 1 , Hagoon Jang 1 , Ji Seul Han 1 , Hahn Nahmgoong 1 , Yoon Jeong Park 1 , Sang Mun Han 1 , Changyun Cho 2 , Sangsoo Lim 3 , Jung-Ran Noh 4 , Won Keun Oh 5 , Chul-Ho Lee 4 , Sun Kim 6 , Jae Bum Kim 1
Affiliation  

Emerging evidence indicates that the accretion of senescent cells is linked to metabolic disorders. However, the underlying mechanisms and metabolic consequences of cellular senescence in obesity remain obscure. In this study, we found that obese adipocytes are senescence-susceptible cells accompanied with genome instability. Additionally, we discovered that SREBP1c may play a key role in genome stability and senescence in adipocytes by modulating DNA-damage responses. Unexpectedly, SREBP1c interacted with PARP1 and potentiated PARP1 activity during DNA repair, independent of its canonical lipogenic function. The genetic depletion of SREBP1c accelerated adipocyte senescence, leading to immune cell recruitment into obese adipose tissue. These deleterious effects provoked unhealthy adipose tissue remodeling and insulin resistance in obesity. In contrast, the elimination of senescent adipocytes alleviated adipose tissue inflammation and improved insulin resistance. These findings revealed distinctive roles of SREBP1c-PARP1 axis in the regulation of adipocyte senescence and will help decipher the metabolic significance of senescence in obesity.



中文翻译:

SREBP1c-PARP1 轴调节脂肪细胞的抗衰老活性并改善肥胖症的代谢失衡

新出现的证据表明,衰老细胞的增生与代谢紊乱有关。然而,肥胖中细胞衰老的潜在机制和代谢后果仍然不清楚。在这项研究中,我们发现肥胖的脂肪细胞是伴随基因组不稳定的衰老敏感细胞。此外,我们发现 SREBP1c 可能通过调节 DNA 损伤反应在脂肪细胞的基因组稳定性和衰老中发挥关键作用。出乎意料的是,SREBP1c 与 PARP1 相互作用并在 DNA 修复过程中增强 PARP1 活性,而与其典型的脂肪生成功能无关。SREBP1c 的基因缺失加速了脂肪细胞的衰老,导致免疫细胞募集到肥胖的脂肪组织中。这些有害影响引发了肥胖中不健康的脂肪组织重塑和胰岛素抵抗。相比之下,衰老脂肪细胞的消除减轻了脂肪组织炎症并改善了胰岛素抵抗。这些发现揭示了 SREBP1c-PARP1 轴在调节脂肪细胞衰老中的独特作用,并将有助于破译肥胖中衰老的代谢意义。

更新日期:2022-04-12
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