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DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria

Ismene Karakasilioti1, Irene Kamileri, Georgia Chatzinikolaou

  • 1Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013 Heraklion, Crete, Greece; Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.

Cell Metabolism
|September 10, 2013
PubMed

Insights

DNA damage triggers chronic inflammation, causing fat tissue loss in lipodystrophies. This study reveals DNA repair defects lead to adipose tissue degeneration via autoinflammation.

Area of Science:

  • Cell Biology
  • Genetics
  • Metabolic Disorders

Background:

  • Lipodystrophies are rare disorders characterized by fat loss.
  • The molecular mechanisms driving lipodystrophy remain largely unknown.

Purpose of the Study:

  • To investigate the role of DNA damage and repair in adipose tissue homeostasis.
  • To elucidate the mechanisms by which DNA damage signaling contributes to fat depletion.

Main Methods:

  • Mice with systemic or adipocyte-specific ERCC1-XPF DNA repair defects were utilized.
  • Gene expression analysis, histological examination, and cellular assays were performed on fat depots and isolated adipocytes.
  • The involvement of ATM signaling in the response to DNA damage was assessed.

Main Results:

  • Mice with ERCC1-XPF defects exhibited hallmarks of lipodystrophy, including reduced adiposity, inflammation, fibrosis, and basement membrane abnormalities.
  • Persistent DNA damage in adipocytes induced pro-inflammatory factors via epigenetic modifications and nuclear receptor complex dissociation.
  • The observed autoinflammatory response was cell-autonomous and dependent on ATM signaling.

Conclusions:

  • Persistent DNA damage triggers a cell-autonomous autoinflammatory response that causes adipose tissue degeneration.
  • This mechanism contributes to the pathogenesis of progressive lipodystrophies and may play a role in aging-related fat loss.

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