Cyclin-dependent Kinase Inhibitor, p21WAF1/CIP1, Is Involved in Adipocyte Differentiation and Hypertrophy, Linking to Obesity, and Insulin Resistance

Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-07, Vol.283 (30), p.21220-21229
Main Authors: Inoue, Noriyuki, Yahagi, Naoya, Yamamoto, Takashi, Ishikawa, Mayumi, Watanabe, Kazuhisa, Matsuzaka, Takashi, Nakagawa, Yoshimi, Takeuchi, Yoshinori, Kobayashi, Kazuto, Takahashi, Akimitsu, Suzuki, Hiroaki, Hasty, Alyssa H., Toyoshima, Hideo, Yamada, Nobuhiro, Shimano, Hitoshi
Format: Article
Language:English
Subjects:
3T3 Cells
Adipocytes - cytology
Animals
Apoptosis
Cell Differentiation
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Cyclin-Dependent Kinase Inhibitor p21 - physiology
Hypertrophy
Insulin Resistance
Lipids and Lipoproteins: Metabolism, Regulation, and Signaling
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
Obesity
Tumor Suppressor Protein p53 - metabolism
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Summary:Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21-/- mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21-/- mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M801824200