SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity

Gung Lee, Ye Young Kim, Hagoon Jang, Ji Seul Han, Hahn Nahmgoong, Yoon Jeong Park, Sang Mun Han, Changyun Cho, Sangsoo Lim, Jung Ran Noh, Won Keun Oh, Chul Ho Lee, Sun Kim, Jae Bum Kim

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)702-718.e5
JournalCell Metabolism
Volume34
Issue number5
DOIs
StatePublished - 3 May 2022

Keywords

  • adipocyte
  • adipose tissue inflammation
  • cellular senescence
  • DNA repair process
  • energy homeostasis
  • insulin resistance
  • obesity
  • PARP1
  • SASP
  • SREBP1c

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