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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1400-1408
Number of pages9
JournalObesity
Volume15
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • Adipogenesis
  • Adipose tissue
  • Molecular mechanisms
  • Mouse models

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Nutrition and Dietetics

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