A functional peroxisome proliferator-activated receptor-γ ligand-binding domain is not required for adipogenesis

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ) is the central regulator of adipogenesis. Although it is the target for several drugs that function as agonist activators, a high affinity endogenous ligand for this receptor that is involved in regulating adipogenesis has yet to be identified. Here, we investigated the requirement for ligand activation of PPARγ in fat cell differentiation, taking advantage of a natural mutant of this receptor that does not bind or become activated by any known natural or synthetic ligand. When ectopically expressed in PPARγ-null fibroblasts, this Q286P allele was able to strongly promote morphological adipogenesis, without any significant difference compared with wild-type PPARγ. In addition, no significant differences were found in the expression of several adipogenic genes between the wild-type and Q286P mutant alleles. To extend our studies to an in vivo setting, we performed subcutaneous injections of PPARγ-expressing fibroblasts into nude mice. We found that both wildtype and Q286P mutant-expressing fibroblasts were able to generate fat pads in the mice. These results suggest that the binding and activation of PPARγ by agonist ligands may not be required for adipogenesis under physiological conditions. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.