Laboratorio de Neuroendocrinología, Instituto Multidisciplinario de Biología Celular (IMBICE), Universidad Nacional de La Plata (UNLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC), Calle 526 1499-1579, B1906APM Tolosa, Buenos Aires, Argentina.
Laboratorio de Proteínas Quinasas y Cáncer, Instituto de Biología y Medicina Experimental (IBYME - CONICET), Vuelta de Obligado 2490, Ciudad Autónoma de Buenos Aires 1428, Argentina.
Life Sci. 2023 Jun 1;322:121652. doi: 10.1016/j.lfs.2023.121652. Epub 2023 Apr 1.
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.
在白色脂肪组织（WAT）中，细胞周期调节剂 CDK4 和 CDK6（CDK4/6）促进脂肪生成并维持脂肪细胞成熟状态。在这里，我们旨在研究它们在 Ucp1 介导的 WAT 脂肪组织产热和米色脂肪细胞生成中的作用。
我们在室温（RT）或寒冷条件下用 CDK4/6 抑制剂 palbociclib 处理小鼠，并分析附睾（腹部）和腹股沟（皮下）WAT 脂肪组织中的产热标志物。我们还评估了体内 palbociclib 处理对基质血管部分（SVF）中米色前体的百分比及其米色成脂潜能的影响。最后，我们用 palbociclib 在体外处理 SVF 和来自 WAT 脂肪组织的成熟脂肪细胞，以研究 CDK4/6 在米色脂肪细胞生成中的作用。
体内 CDK4/6 抑制在 RT 下调产热，并损害了两个 WAT 脂肪组织的冷诱导褐变。它还降低了 SVF 在分化时米色前体的百分比和米色成脂潜能。在体外对照小鼠的 SVF 中直接 CDK4/6 抑制也观察到了类似的结果。重要的是，CDK4/6 抑制也下调了米色分化和脂肪组织来源的脂肪细胞的产热程序。
CDK4/6 调节 WAT 脂肪组织在基础和冷应激条件下的 Ucp1 介导的产热，通过脂肪生成和转分化控制米色脂肪细胞的生成。这表明 CDK4/6 在 WAT 褐变中起着关键作用，可用于对抗肥胖或与褐变相关的高代谢状态，如癌症恶病质。
