Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Maura Agostini, Erik Schoenmakers, Catherine Mitchell, Istvan Szatmari, David Savage, Aaron Smith, Odelia Rajanayagam, Robert Semple, Jian'an Luan, Louise Bath, Anthony Zalin, Mourad Labib, Sudhesh Kumar, Helen Simpson, Dirk Blom, David Marais, John Schwabe, Inês Barroso, Richard Trembath, Nicholas WarehamLaszlo Nagy, Mark Gurnell, Stephen O'Rahilly, Krishna Chatterjee

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128 Citations (Scopus)

Abstract

PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

Original languageEnglish
Pages (from-to)303-311
Number of pages9
JournalCell Metabolism
Volume4
Issue number4
DOIs
Publication statusPublished - Oct 1 2006

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Agostini, M., Schoenmakers, E., Mitchell, C., Szatmari, I., Savage, D., Smith, A., Rajanayagam, O., Semple, R., Luan, J., Bath, L., Zalin, A., Labib, M., Kumar, S., Simpson, H., Blom, D., Marais, D., Schwabe, J., Barroso, I., Trembath, R., ... Chatterjee, K. (2006). Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance. Cell Metabolism, 4(4), 303-311. https://doi.org/10.1016/j.cmet.2006.09.003