The F Box Protein S Phase Kinase-associated Protein 2 Regulates Adipose Mass and Adipocyte Number in Vivo
2007
Cooke, Paul S. | Holsberger, Denise R. | Cimafranca, Melissa A. | Meling, Daryl D. | Beals, Charity M. | Nakayama, Keiko | Nakayama, Keiichi I. | Kiyokawa, Hiroaki
OBJECTIVE: The etiology of some obesity may involve adipocyte hyperplasia. However, the role of adipocyte number in establishing adipose mass is unclear. Cyclin-dependent kinase inhibitor p27 regulates activity of cyclin/cyclin-dependent kinase complexes responsible for cell cycle progression. This protein is critical for establishing adult adipocyte number, and p27 knockout increases adult adipocyte number. The SCF (for Skp1-Cullin-F-box protein) complex targets proteins such as p27 for ubiquitin-proteosome degradation; the F box protein S phase kinase-associated protein 2 (Skp2), a component of the SCF complex, specifically recognizes p27 for degradation. We used Skp2 knockout (Skp2⁻/⁻) mice to test whether Skp2 loss decreased adipose mass and adipocyte number. RESEARCH METHODS AND PROCEDURES: We measured body weight, adipose mass, adipocyte diameter and number, and glucose tolerance in wild-type (WT), Skp2⁻/⁻, and p27⁻/⁻Skp2⁻/⁻ mice. Mouse embryo fibroblasts (MEFs) from WT and Skp2⁻/⁻ fetuses were differentiated to determine whether Skp2 directly affected adipogenesis. RESULTS: Skp2⁻/⁻ mice had a 50% decrease in both subcutaneous and visceral fat pad mass and adipocyte number; these decreases exceeded those in body weight, kidney, or muscle. To test the hypothesis that Skp2 effects on adipocyte number involved p27 accumulation, we used p27⁻/⁻Skp2⁻/⁻ double knockout mice. The Skp2⁻/⁻ decrements in adipocyte number and fat pad mass were totally reversed in p27⁻/⁻Skp2⁻/⁻ mice. Adipogenesis was inhibited in MEFs from Skp2⁻/⁻ vs. WT mice, and this inhibition was absent in MEFs from p27⁻/⁻Skp2⁻/⁻ mice. DISCUSSION: Our results indicate that Skp2 regulates adipogenesis and ultimate adipocyte number in vivo; thus, Skp2 may contribute to obesity involving adipocyte hyperplasia.
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