State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, People's Republic of China.
Department of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China.
Diabetes. 2018 Nov;67(11):2397-2409. doi: 10.2337/db18-0684. Epub 2018 Aug 21.
Profound loss and senescence of adipose tissues are hallmarks of advanced age, but the underlying cause and their metabolic consequences remain obscure. Proper function of the murine double minute 2 (MDM2)-p53 axis is known to prevent tumorigenesis and several metabolic diseases, yet its role in regulation of adipose tissue aging is still poorly understood. In this study, we show that the proximal p53 inhibitor MDM2 is markedly downregulated in subcutaneous white and brown adipose tissues of mice during aging. Genetic disruption of MDM2 in adipocytes triggers canonical p53-mediated apoptotic and senescent programs, leading to age-dependent lipodystrophy and its associated metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, hyperlipidemia, and energy imbalance. Surprisingly, this lipodystrophy mouse model also displays premature loss of physiological integrity, including impaired exercise capacity, multiple organ senescence, and shorter life span. Transplantation of subcutaneous fat rejuvenates the metabolic health of this aging-like lipodystrophy mouse model. Furthermore, senescence-associated secretory factors from MDM2-null adipocytes impede adipocyte progenitor differentiation via a non-cell-autonomous manner. Our findings suggest that tight regulation of the MDM2-p53 axis in adipocytes is required for adipose tissue dynamics and metabolic health during the aging process.
脂肪组织的深度损耗和衰老，是衰老的显著特征，但其中的根本原因及其代谢后果仍然难以捉摸。已知鼠双微体 2（MDM2）-p53 轴的正常功能可预防肿瘤发生和多种代谢疾病，但它在调节脂肪组织衰老中的作用仍知之甚少。在这项研究中，我们表明，在衰老过程中，小鼠的皮下白色和棕色脂肪组织中，近端 p53 抑制剂 MDM2 的表达明显下调。脂肪细胞中 MDM2 的基因缺失会触发经典的 p53 介导的凋亡和衰老程序，导致与年龄相关的脂肪损耗及其相关的代谢紊乱，包括 2 型糖尿病、非酒精性脂肪肝疾病、血脂异常和能量失衡。令人惊讶的是，这种脂肪损耗小鼠模型还表现出生理完整性的过早丧失，包括运动能力受损、多个器官衰老和寿命缩短。皮下脂肪的移植可恢复这种类似衰老的脂肪损耗小鼠模型的代谢健康。此外，来自 MDM2 缺失脂肪细胞的衰老相关分泌因子通过非细胞自主方式阻碍脂肪细胞祖细胞的分化。我们的研究结果表明，脂肪细胞中 MDM2-p53 轴的严格调控，对于衰老过程中脂肪组织的动态和代谢健康是必需的。
