Loss of cyclin-dependent kinase inhibitors produces adipocyte hyperplasia and obesity.
Adipocyte hyperplasia is characteristic of some forms of human obesity, but the role of adipocyte number in obesity and how normal adipocyte number is established are unclear. Preadipocytes proliferate and then differentiate to become mitotically quiescent adipocytes. This involves exit from the cell cycle, a process regulated by cell cycle inhibitors such as the cyclin-dependent kinase inhibitors (CDKIs) p27 and p21. 3T3-L1 preadipocytes show marked changes in p27 and p21 during differentiation, suggesting CDKIs may regulate establishment of adipocyte number in vivo. To study the role of these CDKIs in adipogenesis, we analyzed adult p27 knockout (p27KO), p21 knockout (p21KO), p27/p21 double knockout (DBKO), and wild-type (WT) mice. Adult DBKO mice weighed 100% more and had fourfold increases in body fat percentage compared with WT. Fat pad weights were increased 80, 90, and 500% in p27KO, p21KO, and DBKO mice, respectively, compared with WT. Adipocyte numbers of p27KO, p21KO, and DBKO mice were 1.9-, 1.7-, and 6.1-fold, respectively, that of WT; adipocyte size was not increased. DBKO mice showed glucose intolerance, insulin insensitivity, hepatic steatosis and dyslipidemia; gradations of these effects occurred in p27KO and p21KO mice. In conclusion, p27KO and p21KO mice are obese because of adipocyte hyperplasia, and DBKO mice have further increases in obesity and adipocyte hyperplasia, indicating that their functions in establishing adipocyte number are not redundant. p27 and p21 are major regulators of adipocyte number in vivo, and knockouts lacking one or both of these proteins provide models for producing adipocyte hyperplasia and understanding its metabolic consequences.
Department of Veterinary Biosciences, University of Illinois-Urbana, Urbana, Illinois 61802, USA.
Afia
A
Naaz
Denise R
DR
Holsberger
Gary A
GA
Iwamoto
Amanda
A
Nelson
Hiroaki
H
Kiyokawa
Paul S
PS
Cooke
D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D015430:Weight Gain
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27