Edinburgh Research Explorer Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance

PPAR g is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPAR g in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPAR g coactivators and inhibit coexpressed wild-type receptor. Expression of PPAR g 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 g action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting

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