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 language | English (US) |
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Pages (from-to) | 303-311 |
Number of pages | 9 |
Journal | Cell Metabolism |
Volume | 4 |
Issue number | 4 |
DOIs | |
State | Published - Oct 2006 |
Externally published | Yes |
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology