CDK4/6 are necessary for UCP1-mediated thermogenesis of white adipose tissue

In white adipose tissue (WAT) the cell cycle regulators CDK4 and CDK6 (CDK4/6) promote adipogenesis and maintain the adipocyte mature state. Here we aimed to investigate their role in the Ucp1-mediated thermogenesis of WAT depots and in the biogenesis of beige adipocytes. We treated mice with the CDK4/6 inhibitor palbociclib at room temperature (RT) or cold and analyzed thermogenic markers in the epididymal (abdominal) and inguinal (subcutaneous) WAT depots. We also assessed the effect of in vivo palbociclib-treatment on the percentage of beige precursors in the stroma vascular fraction (SVF), and on its beige adipogenic potential. Finally, we treated SVFs and mature adipocytes from WAT depots with palbociclib in vitro to study the role of CDK4/6 in beige adipocytes biogenesis. In vivo CDK4/6 inhibition downregulated thermogenesis at RT and impaired cold-induced browning of both WAT depots. It also reduced the percentage of beige precursors and beige adipogenic potential of the SVF upon differentiation. A similar result was observed with direct CDK4/6 inhibition in the SVF of control mice in vitro. Importantly, CDK4/6 inhibition also downregulated the thermogenic program of beige differentiated- and depots-derived adipocytes. CDK4/6 modulate Ucp1-mediated thermogenesis of WAT depots in basal and cold-stressing conditions controlling beige adipocytes biogenesis by adipogenesis and transdifferentiation. This shows a pivotal role of CDK4/6 in WAT browning that could be applied to fight obesity or browning-associated hypermetabolic conditions such as cancer cachexia.