p53 Functions in Adipose Tissue Metabolism and Homeostasis.
p53 Functions in Adipose Tissue Metabolism and Homeostasis.
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DOI：
10.3390/ijms19092622
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发表时间：
2018-09-04
影响因子：
5.6
通讯作者：
Prokesch A
中科院分区：
文献类型：
--
作者：
Krstic J;Reinisch I;Schupp M;Schulz TJ;Prokesch A
作为一种肿瘤抑制因子和癌症中最常见的突变基因，p53是医学研究中描述得最好的分子之一。由于癌症在大多数情况下是一种与年龄有关的疾病，p53从早期的多细胞生物到人类都如此强烈地保守，这似乎是自相矛盾的。一种与肿瘤抑制不直接相关的功能，如非转化细胞的代谢调节，可以解释这种选择压力。虽然p53在细胞代谢中的作用逐渐显现，但解剖p53的组织和细胞特异性作用及其下游信号通路是必要的。在这篇综述中，我们将重点关注p53对脂肪细胞发育、功能和维持的影响，以及白色和棕色脂肪组织（AT）中p53水平改变与全身能量稳态的原因和后果。虽然在高脂肪饮食下，由于能量消耗增加，p53敲除小鼠全身体重和脂肪量增加较少，但在脂肪细胞中特异性修饰p53表达可以获得更精细的见解：(1)p53是体外脂肪形成的负调节因子；(2)在饮食诱导和遗传性肥胖小鼠模型以及肥胖人群中，白色AT中的p53水平升高；(3)功能上，白色AT中p53的升高会增加衰老和慢性炎症，加重全身胰岛素抵抗；(4)褐色AT的正常发育不需要p53；(5)当高脂饮食小鼠棕色AT中的p53被激活时，它会增加棕色AT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知途径中的关键角色。因此，尽管存在相互矛盾的发现和不同密度的证据，p53在脂肪细胞和ATs中的一些功能已经出现，将p53定位为ATs中必不可少的调节中心。未来的研究需要利用更复杂的体内模型系统，并应确定at特异性的p53靶基因和不同（营养）挑战下的下游途径，以确定新的治疗靶点来抑制代谢性疾病。
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 p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro 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 in vivo 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.
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影响因子：
4.6
作者：
Reiling E;Speksnijder EN;Pronk AC;van den Berg SA;Neggers SJ;Rietbroek I;van Steeg H;Dollé ME
通讯作者：
Dollé ME
影响因子：
4.3
作者：
Cinti S
通讯作者：
Cinti S
影响因子：
4.8
作者：
Bogazzi, Fausto;Raggi, Francesco;Martino, Enio
通讯作者：
Martino, Enio
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
4.3
作者：
Bowers, Robert R.;Lane, M. Daniel
通讯作者：
Lane, M. Daniel