Editors' ChoiceNuclear Receptors

Ligand Not Required?

Science Signaling  09 Sep 2008:
Vol. 1, Issue 36, pp. ec316
DOI: 10.1126/scisignal.135ec316

Peroxisome proliferator-activated receptor-γ (PPARγ) is necessary for adipogenesis--ectopic expression drives preadipocytes to differentiate into adipocytes, and cells lacking PPARγ fail to form adipocytes. Although several endogenous molecules, as well as synthetic molecules, can bind to and increase the activity of PPARγ, which is a member of the nuclear receptor family, a biologically relevant endogenous ligand has not been conclusively identified. Walkey and Spiegelman compared the agonist-binding properties and adipogenic activities of wild-type PPARγ and two mutants---Q286P and E499Q, both of which disrupt agonist binding. E499Q also disrupts the AF-2 domain, which serves as a docking site for coactivators in nuclear receptors. Wild-type PPARγ and Q286P exhibited basal transcriptional activity when transfected into HEK293 cells along with a reporter gene; E499Q had very little basal activity. Only transcriptional activity of the wild-type PPARγ was stimulated by the addition of various agonists. Despite the lack of stimulation by agonists, introduction of Q286P into PPARγ-null fibroblasts restored their ability to differentiate into adipocytes based on morphological characteristics and the induction of the expression of genes associated with the adipocyte phenotype. In contrast, the E499Q mutant failed to restore adipogenesis to the PPARγ-null cells. Fat pads formed when cells expressing either the wild-type PPARγ or Q286P were injected into the skin of nude mice. These data suggest that a ligand may not be necessary for PPARγ to promote adipogenesis.

C. J. Walkey, B. M. Spiegelman, A functional peroxisome proliferator-activated receptor-γ ligand-binding domain is not required for adipogenesis. J. Biol. Chem. 283, 24290-24294 (2008). [Abstract] [Full Text]