Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Am J Physiol Endocrinol Metab. 2011 Dec;301(6):E1130-42. doi: 10.1152/ajpendo.00092.2011. Epub 2011 Aug 16.
The function of the tumor suppressor promyelocytic leukemia (PML) protein is disrupted in promyelocytic leukemia. PML has been reported to function as a negative regulator of mTOR (mammalian target of rapamycin) and nuclear Akt under some conditions. mTOR and Akt pathways regulate a diverse array of pathways, including those that control insulin signaling, energy metabolism, growth, cellular survival, and lifespan. Although the PML-mTOR/Akt link suggests that PML may have metabolic functions in the whole organism, very little is known about the metabolic functions of PML. Here we report that PML(-/-) mice did not show any significant metabolic defects. There was no impairment in the mTOR/Akt or AMPK signaling in white adipose tissue, liver, or muscle. However, despite having normal food intake and activity levels, PML(-/-) mice gained body weight faster and had more fat mass, particularly subcutaneous fat mass, in the diet-induced obesity model. Using in vitro adipogenesis models, we discovered that PML is a suppressor of adipogenesis. PML expression decreased during adipogenesis and was undetectable in fully differentiated adipocytes. Loss of PML increased expression of the adipogenic transcription factors CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ. We found that the Sirt1-NCor-SMRT corepressor complex, which represses pparg transcription, does not bind to the pparg promoter efficiently upon PML depletion. On the basis of these findings, we propose that PML is a negative regulator of the adipogenic transcription factors and that, in times of energy excess, PML may limit fat accumulation by suppressing the differentiation of preadipocytes into adipocytes.
早幼粒细胞白血病（PML）蛋白的抑癌功能在早幼粒细胞白血病中受到破坏。据报道，在某些条件下，PML 作为哺乳动物雷帕霉素靶蛋白（mTOR）和核 Akt 的负调节剂发挥作用。mTOR 和 Akt 途径调节多种途径，包括控制胰岛素信号、能量代谢、生长、细胞存活和寿命的途径。尽管 PML-mTOR/Akt 联系表明 PML 可能在整个生物体中具有代谢功能，但对 PML 的代谢功能知之甚少。在这里，我们报告 PML(-/-) 小鼠没有表现出任何明显的代谢缺陷。在白色脂肪组织、肝脏或肌肉中，mTOR/Akt 或 AMPK 信号没有受损。然而，尽管 PML(-/-) 小鼠的食物摄入量和活动水平正常，但它们在饮食诱导的肥胖模型中体重增加更快，并且脂肪量更多，特别是皮下脂肪量更多。使用体外脂肪生成模型，我们发现 PML 是脂肪生成的抑制剂。在脂肪生成过程中，PML 的表达降低，在完全分化的脂肪细胞中无法检测到。PML 的缺失增加了脂肪生成转录因子 CCAAT/增强子结合蛋白-α和过氧化物酶体增殖物激活受体-γ 的表达。我们发现，沉默信息调节因子 1-NCor-SMRT 核心抑制复合物，它抑制 pparg 转录，在 PML 耗尽时不能有效地结合到 pparg 启动子上。基于这些发现，我们提出 PML 是脂肪生成转录因子的负调节剂，并且在能量过剩时，PML 可能通过抑制前脂肪细胞分化为脂肪细胞来限制脂肪积累。
