Skip to Main content Skip to Navigation
Journal articles

Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans.

Abstract : Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARgamma signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARgamma in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARgamma heterodimerization partner retinoid X receptor alpha (RXRalpha), but not RXRbeta, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRalpha proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARgamma-RXRbeta heterodimers, but not PPARgamma-RXRalpha complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRalpha/RXRbeta ratio resulted in increased PPARgamma responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRalpha initiated by UCH-L1 upregulation modulates the relative affinity of PPARgamma heterodimers for SMRT and their responsiveness to PPARgamma agonists, ultimately activating the PPARgamma-controlled gene network in visceral WAT of obese animals and humans.
Document type :
Journal articles
Complete list of metadatas

Cited literature [57 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00472906
Contributor : Marie-Hélène Derudas <>
Submitted on : Tuesday, April 13, 2010 - 3:30:47 PM
Last modification on : Friday, July 17, 2020 - 10:54:05 AM
Long-term archiving on: : Friday, October 19, 2012 - 1:55:08 PM

File

Lefebvre_et_al_JCI.pdf
Files produced by the author(s)

Identifiers

Collections

Citation

Bruno Lefebvre, Yacir Benomar, Aurore Guédin, Audrey Langlois, Nathalie Hennuyer, et al.. Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans.. Journal of Clinical Investigation, American Society for Clinical Investigation, 2010, 120 (5), pp.1454-68. ⟨10.1172/JCI38606⟩. ⟨inserm-00472906⟩

Share

Metrics

Record views

387

Files downloads

345