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

Abstract

Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21 WAF1/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.The process of adipocyte differentiation has been extensively characterized in cultures of preadipocyte clonal cell lines such as mouse 3T3-L1 and 3T3-F442A (1, 2). Adipogenesis requires a sequence of events including growth arrest of proliferating preadipocytes, coordinated reentry into the cell cycle with limited clonal expansion, and growth arrest before terminal differentiation during which lipid accumulation occurs. Thus, it is reasonable to assume that factors involved in cell cycle regulation may have important roles in the adipocyte differentiation process. Cell cycle progression in mammals is governed by various complexes of cyclins and cyclin-dependent kinases (CDKs) 2 as well as their inhibitors, of which p21 and p27 are the most widely studied. It was previously suggested that expression of p21 and p27 is changed during the adipogenesis (3). p21 has been reported to be induced by Foxo1 and has been implicated in entry of adipocytes into the clonal expansion phase of adipogenesis; meanwhile, p27 is critical for adipocyte hyperplasia (3-5). The expression of both p21 and p27 is altered during adipocyte differentiation; however, their precise role in adipogenesis, especially at the time of terminal differentiation, remains unclear.Obesity is caused by over-nutrition and decreased physical activity and is characterized by excess storage of lipids in adipose tissue, which can be accounted for by both adipocyte hyperplasia and hypertrophy. Obesity often precedes insulin resistance and precipitates type 2 diabetes and cardiovascular diseases (6). Impaired adipocyte differentiation is also related to insulin resistance. Based upon the potential roles of CDK inhibitors in cell cycle progression and apoptosis, it is reasonable t...

PPARγ ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation

“…2A ). Lack of p21 has previously been associated with accelerated hormonally induced adipogenesis and hyperplasic adipose tissue ( 14,15 ). We therefore speculated whether p21-defi cient MEFs would recapitulate the spontaneous adi pogen esis observed in p53-defi cient MEFs.…”

“…Mice lacking the two cyclin-dependent kinase inhibitors (CDKIs) p21 and p27 display adipose tissue hyperplasia ( 14 ). Also, MEFs lacking p21 undergo accelerated adipogenesis, although the CDKI was required for the survival of mature adipocytes ( 15 ).…”

Circadian variations in gene expression in rat abdominal adipose tissue and relationship to physiology

“…For example, cyclin-dependent kinase inhibitor 1A (CDKN1A, also called p21) is a negative regulator of cell cycle progression by inhibiting the activity of cyclin-Cdk2 and cyclin-CDK4 complexes in the G 1 -to-S phase transition (6). CDKN1A positively regulates adipocyte differentiation, and knockdown of this gene is found to suppress the differentiation process (28). Another example is Wee1 kinase protein, which is a critical regulator of the G 2 -to-M transition checkpoint by inhibiting the activity of cyclin B1-CDK1 complex (6).…”

Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method

“…4B, this subnet composed by STRAP and nodes connected to it, such as p21 and p53. p21 is known to promote adipose tissue expansion and leads to insulin resistance (Inoue et al, 2008), and many proteins affecting the insulin pathway are regulated by p53 (Feng et al, 2007). This subnet indicates that Snitrosation of STRAP may play an indirect role in diabetes via p21 and p53.…”