Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Department of Cell Biology, Histology and Embryology, Medical University Graz, 8010 Graz, Austria.
Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
Int J Mol Sci. 2018 Sep 4;19(9):2622. doi: 10.3390/ijms19092622.
As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue- and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases.
作为肿瘤抑制因子和癌症中最常发生突变的基因，p53 是医学研究中描述得最清楚的分子之一。由于癌症在大多数情况下是一种与年龄相关的疾病，因此 p53 从早期多细胞生物到人类都如此强烈地保守，这似乎有些矛盾。一个与肿瘤抑制无关的功能，例如非转化细胞代谢的调节，可能可以解释这种选择压力。虽然 p53 在细胞代谢中的这种作用逐渐显现出来，但解析 p53 及其下游信号通路在组织和细胞特异性中的作用至关重要。在这篇综述中，我们重点介绍了报道 p53 对脂肪细胞发育、功能和维持的影响的研究，以及白色和棕色脂肪组织（AT）中 p53 水平改变的原因和后果与全身能量稳态的关系。虽然全身 knockout 小鼠由于能量消耗增加，在高脂肪饮食下体重和脂肪量增加较少，但专门修饰脂肪细胞中的 表达则产生了更精细的见解：（1）p53 是脂肪生成的负调节剂；（2）饮食诱导和遗传肥胖小鼠模型以及肥胖人群的白色 AT 中 p53 水平升高；（3）从功能上讲，白色 AT 中升高的 p53 会增加衰老和慢性炎症，从而加重全身胰岛素抵抗；（4）p53 不是棕色 AT 正常发育所必需的；（5）当高脂饮食喂养的小鼠的棕色 AT 中激活 p53 时，它会增加棕色 AT 的温度和棕色 AT 标记基因的表达，从而有助于减少脂肪量的积累。此外，p53 越来越被认为是营养感应途径中的关键参与者。因此，尽管存在矛盾的发现和证据密度的差异，p53 在脂肪细胞和 AT 中的几个功能已经显现出来，使 p53 成为 AT 中的一个重要调节枢纽。未来的研究需要利用更复杂的 模型系统，并在不同（营养）挑战下确定一组特定于 AT 的 p53 靶基因和下游途径，以确定新的治疗靶点来遏制代谢疾病。
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