在白色脂肪组织（WAT）中，细胞周期调节蛋白CDK4和CDK6（CDK4/6）促进脂肪生成并维持脂肪细胞的成熟状态。我们的研究旨在探究它们在Ucp1介导的WAT沉积物热发生和细胞生成中的作用。我们在室温（RT）或寒冷条件下用CDK4/6抑制剂Palbociclib处理小鼠，并分析在附睾（腹部）和腹股沟（皮下）WAT沉积物中的热成像标记。我们还评估了体内Palbociclib治疗对基质血管组分（SVF）中皮质前体细胞的百分比和其棕色成脂潜能的影响。最后，我们在体外用Palbociclib处理WAT沉积物的SVFs和成熟的脂肪细胞，以研究CDK4/6在棕色脂肪细胞生成中的作用。体内CDK4/6抑制剂可以降低RT的热发生和双向WAT的冷诱导棕色化能力。它还减少基质血管组分的皮质前体细胞的百分比和棕色成脂潜能。在控制小鼠的SVF中进行直接CDK4/6抑制，在体内也观察到了类似的结果。重要的是，CDK4/6抑制还下调了棕色分化和沉积物来源的脂肪细胞的热发生程序。CDK4/6通过脂肪生成和转分化，在基础和冷应激条件下调节WAT沉积物的Ucp1介导的热发生和棕色脂肪生成。这表明CDK4/6在WAT棕化中具有关键作用，可应用于对抗肥胖症或棕化相关的高代谢疾病，如癌症恶病质。Copyright © 2023 Elsevier Inc.发表。

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 the 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.Copyright © 2023. Published by Elsevier Inc.