title: The F box protein S phase kinase-associated protein 2 regulates adipose mass and adipocyte number in vivo.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Our results indicate that Skp2 regulates adipogenesis and ultimate adipocyte number in vivo; thus, Skp2 may contribute to obesity involving adipocyte hyperplasia.
authors.affiliation: Department of Veterinary Biosciences, 2001 South Lincoln Ave, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA. p-cooke@uiuc.edu
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cooke
authors.forename: Denise R
authors.initials: DR
authors.lastname: Holsberger
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Cimafranca
authors.forename: Daryl D
authors.initials: DD
authors.lastname: Meling
authors.forename: Charity M
authors.initials: CM
authors.lastname: Beals
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000033:anatomy & histology* / Q000196:embryology; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000502:physiology; D005260:Female; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D044783:F-Box Proteins; D044786:S-Phase Kinase-Associated Proteins