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.
|Original language||English (US)|
|Number of pages||13|
|State||Published - Sep 3 2013|
Bibliographical noteFunding Information:
This work was supported by Heracleitus II, NSRF-ESPA 2007-2013 (KA3396); Cooperation I, NSRF-ESPA 2007-2013 (901-13/11/2009); GenAge, NSRF-ESPA 2007-2013 (380228); miREG, NSRF-ESPA 2007-2013 (380247); TagNER, NSRF-ESPA 2007-2013 (45); ELKE, University of Crete (901-13/11/2009); the aDDRess, FP7 Marie Curie ITN (316390); CodeAge, FP7 Marie Curie ITN (316354); and Marriage, FP7 Marie Curie ITN (316964). I.K. is supported by the Maria-Michail Manassakis fellowship. A.R.R. and L.J.N. were supported by NIH (ES016114). G.A.G. is supported by the EMBO Young Investigator program. None of the authors of this work have a financial interest related to this work.