Skp2, the substrate-binding subunit of an SCF ubiquitin ligase complex, is a key regulator of cell cycle progression that targets substrates for degradation by the 26S proteasome. We have now shown that ablation of Skp2 in primary mouse embryonic fibroblasts (MEFs) results both in impairment of adipocyte differentiation and in the accumulation of the cyclin-dependent kinase inhibitor p27(Kip1), a principal target of the SCFSkp2 complex. Genetic ablation of p27(Kip1) in MEFs promoted both lipid accumulation and adipocyte-specific gene expression. However, depletion of p27(Kip1) by adenovirus-mediated RNA interference failed to correct the impairment of adipocyte differentiation in Skp2 (/) MEFs. In contrast, troglitazone, a high-affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma), largely restored lipid accumulation and PPAR gamma gene expression in Skp2 I MEFs. Our data Suggest that Skp2 plays an essential role in adipogenesis in MEFs in a manner that is at least in part independent of regulation of p27(Kip1) expression. (C) 2008 Elsevier Inc. All rights reserved.