Genome-wide association studies have established that single nucleotide polymorphisms and loss-of-function mutations in the cyclin-dependent kinase Inhibitor 2A (CDKN2A) locus affect glucose homeostasis, insulin sensitivity and T2D. Decreased DNA methylation at the CDKN2A gene is associated with a higher risk to develop obesity and related diseases later in life. The human CDKN2A locus encodes for two proteins, p16INK4a a Cyclin Dependent Kinase inhibitory (CDKI) protein and the p53 regulatory protein p14ARF (p19ARF in mice). p16 INK4a is a potent CDKI preventing binding of CDK4/6 to Cyclin D whereas p14ARF mainly exerts it anti-proliferative activity via the inhibition of MDM2, an ubiquitin-ligase that modulates the activity of the tumor suppressor p53. In adipose tissue, besides to its cell cycle regulator functions (i.e. proliferation or senescence), the CDKN2A locus also controls the commitment of stem cells to the brown-like type fate and mature adipocyte energy metabolism, suggesting new physiological functions. We have recently demonstrated that mice with a germline disruption of the Cdkn2a gene (Cdkn2a-/-) fed a HF diet are protected against DIO by increasing thermogenesis via inguinal (ing)WAT beiging resulting in improved insulin sensitivity. We also observed that CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Silencing CDKN2A expression during human-induced pluripotent stem cells (hiPSCs) adipogenic differentiation results in reprogramming of brown-like adipocytes by promoting UCP1 expression and beiging markers, suggesting a cell-autonomous action. To assess whether beiging is cell-autonomously controlled by Cdkn2a and due to transdifferentiation of mature adipocyte and/or recruitment of APs, we have analyzed the effect of Cdkn2a deficiency restricted to mature adipocytes using AdipoQ-CRE mice bred with Cdkn2a floxed animals (Cdkn2aad-/-). Our preliminary results demonstrate that, although these mice have improved glucose tolerance and are resistant to DIO, no beiging was observed in ingWAT. Interestingly, RNA-seq analysis of hiPSCs in which CDKN2A silencing was performed at the progenitor stage highlighted an enrichment of the browning process pathway in 10 days-differentiated 3D adipospheres. These data suggest that Cdkn2a may not control AT plasticity through transdifferentiation in fully differentiated adipocytes, raising the hypothesis of potential effects in progenitor cells.