oa Exploring the SIRT1/P53 Pathway in Adipocytes Hyperplasia

The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. Knowledge on what drives adipocyte hyperplasia in obesity remains limited. SIRT1, a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues counteracting obesity. By stably knocking down SIRT1 in mouse 3T3-L1 preadipocytes, we demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes and mitotic clonal expansion (MCE) in differentiating adipocytes. Quantitative proteomics reveals that the p53 pathways is altered to drive enhanced proliferation in SIRT1 knockdown preadipocytes. Moreover, p53 is hyperacetylated, p27 is reduced and CDK2 is activated in SIRT1-silenced preadipocytes. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced MCE accompanied with reduced p27, increased C/EBPβ, and also have hyperacetylated p53, leading to hyperplastic and dysfunctional adipocytes. Better understanding of the molecular mechanisms of adipocyte hyperplasia will open new venues towards understanding obesity.