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

Agostini, Maura, Schoenmakers, Erik, Mitchell, Catherine, Szatmari, Istvan, Savage, David, Smith, Aaron, Rajanayagam, Odelia, Semple, Robert, Luan, Jian'an, Bath, Louise, Zalin, Anthony, Labib, Mourad, Kumar, Sudhesh, Simpson, Helen, Blom, Dirk, Marais, David, Schwabe, John, Barroso, Inês, Trembath, Richard, Wareham, Nicholas, Nagy, Laszlo, Gurnell, Mark, O'Rahilly, Stephen and Chatterjee, Krishna (2006) Non-DNA binding, dominant-negative, human PPAR gamma mutations cause lipodystrophic insulin resistance. Cell Metabolism, 4 4: 303-311. doi:10.1016/j.cmet.2006.09.003


Author Agostini, Maura
Schoenmakers, Erik
Mitchell, Catherine
Szatmari, Istvan
Savage, David
Smith, Aaron
Rajanayagam, Odelia
Semple, Robert
Luan, Jian'an
Bath, Louise
Zalin, Anthony
Labib, Mourad
Kumar, Sudhesh
Simpson, Helen
Blom, Dirk
Marais, David
Schwabe, John
Barroso, Inês
Trembath, Richard
Wareham, Nicholas
Nagy, Laszlo
Gurnell, Mark
O'Rahilly, Stephen
Chatterjee, Krishna
Title Non-DNA binding, dominant-negative, human PPAR gamma mutations cause lipodystrophic insulin resistance
Journal name Cell Metabolism   Check publisher's open access policy
ISSN 1550-4131
Publication date 2006-10
Sub-type Article (original research)
DOI 10.1016/j.cmet.2006.09.003
Volume 4
Issue 4
Start page 303
End page 311
Total pages 9
Place of publication Cambridge
Publisher Cell Press
Language eng
Subject 0601 Biochemistry and Cell Biology
Abstract PPAR gamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPAR gamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPAR gamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPAR gamma 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 PPAR gamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.
Keyword Cell Biology
Endocrinology & Metabolism
Proliferator-activated-receptor
Thyroid-hormone Receptor
Familial Partial Lipodystrophy
Nuclear Receptors
Gene-expression
Antidiabetic Thiazolidinedione
Transcription Factor
Responsive Element
In-vitro
Coactivator
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 25 Jan 2008, 16:57:52 EST