Cell Metabolism
Volume 18, Issue 3, 3 September 2013, Pages 403-415
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Article
DNA Damage Triggers a Chronic Autoinflammatory Response, Leading to Fat Depletion in NER Progeria

https://doi.org/10.1016/j.cmet.2013.08.011Get rights and content
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Highlights

  • ERCC1-defective mice show signs of lipodystrophy leading to fat depletion

  • Persistent DDR triggers chronic autoinflammation in aP2-Ercc1F/− fat depots

  • DNA damage triggers the transcriptional derepression of proinflammatory factors

  • ATM is required for the activation of proinflammatory responses in adipocytes

Summary

Lipodystrophies represent a group of heterogeneous disorders characterized by loss of fat tissue. However, the underlying mechanisms remain poorly understood. Using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, we show that DNA damage signaling triggers a chronic autoinflammatory response leading to fat depletion. Ercc1−/− and aP2-Ercc1F/− fat depots show extensive gene expression similarities to lipodystrophic Pparγldi/+ animals, focal areas of ruptured basement membrane, the reappearance of primary cilia, necrosis, fibrosis, and a marked decrease in adiposity. We find that persistent DNA damage in aP2-Ercc1F/− fat depots and in adipocytes ex vivo triggers the induction of proinflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor corepressor complexes from promoters; the response is cell autonomous and requires ataxia telangiectasia mutated (ATM). Thus, persistent DNA damage-driven autoinflammation plays a causative role in adipose tissue degeneration, with important ramifications for progressive lipodystrophies and natural aging.

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