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National Institute of Environmental Health Sciences

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Publication Detail

Title: The F box protein S phase kinase-associated protein 2 regulates adipose mass and adipocyte number in vivo.

Authors: Cooke, Paul S; Holsberger, Denise R; Cimafranca, Melissa A; Meling, Daryl D; Beals, Charity M; Nakayama, Keiko; Nakayama, Keiichi I; Kiyokawa, Hiroaki

Published In Obesity (Silver Spring), (2007 Jun)

Abstract: 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.

PubMed ID: 17557977 Exiting the NIEHS site

MeSH Terms: Adipocytes/cytology*; Adipogenesis/genetics; Adipose Tissue/anatomy & histology*; Adipose Tissue/embryology; Animals; Cell Count; Cells, Cultured; F-Box Proteins/physiology; Female; Glucose Tolerance Test; Insulin Resistance; Mice; Mice, Knockout; Organ Size; S-Phase Kinase-Associated Proteins/genetics; S-Phase Kinase-Associated Proteins/physiology*

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