Overexpression of p53 accelerates puberty in high-fat diet-fed mice through Lin28/let-7 system
Overexpression of p53 accelerates puberty in high-fat diet-fed mice through Lin28/let-7 system
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p53 的过度表达通过 Lin28/let-7 系统加速高脂饮食喂养小鼠的青春期
DOI：
10.1177/1535370220961320
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发表时间：
2021-01-01
影响因子：
3.2
通讯作者：
Chen, Linqi
中科院分区：
文献类型：
--
作者：
Chen, Ting;Chen, Cailong;Chen, Linqi
高脂肪摄入是全球儿童肥胖症发病率激增的重要原因之一。肥胖和高脂肪摄入可导致下丘脑-垂体-性腺轴的过早激活和中枢性性早熟。青春期的开始是由包含重叠和相互作用的基因网络的神经内分泌机制控制的。后者包含五个主要的转录水平枢纽，其中转录因子p53是一种公认的肿瘤抑制蛋白，在肥胖和代谢紊乱中也起着至关重要的作用。在目前的研究中，我们重复了先前的观察，即高脂肪饮食促进啮齿动物的阴道开口，并通过证明高脂肪饮食小鼠下丘脑中p53的表达高于正常食物喂养的小鼠来扩展这些发现。更重要的是，在高脂饮食小鼠中，下丘脑特异性过表达p53可以使阴道开放更早，而抑制p53表达相对延迟阴道开放。在高脂饮食小鼠中，c-Myc和Lin 28 b水平增加，而let-7a mRNA水平降低。在高脂饮食小鼠中，p53过表达降低了c-Myc和Lin 28 b mRNA和蛋白水平，而升高了let-7a mRNA水平。pifithrin-α抑制p53表达可升高高脂饮食小鼠的c-Myc和Lin 28 b水平，但降低let-7a水平。结论：高脂肪摄入可通过上调下丘脑p53蛋白的表达而加速青春期的开始。p53过表达可能部分通过c-Myc/Lin 28/let-7系统促进下丘脑-垂体-性腺轴的激活。高脂肪摄入和随后的肥胖与青春期过早开始有关，但确切的神经内分泌机制仍不清楚。转录因子p53被预测为控制青春期开始的基因网络的中心枢纽。此外，p53在代谢中也起着重要作用。在这里，我们探讨了p53在小鼠下丘脑喂养高脂饮食（HFD），这表明表达上调。此外，我们还发现过表达p53可能部分通过c-Myc/Lin 28/let-7系统促进下丘脑-垂体-性腺轴（HPG）的激活。这些结果有助于加深我们对代谢调节与青春期启动控制之间相互作用的理解，并可能揭示肥胖相关性中枢性早熟的神经内分泌机制。
High fat intake is one of the most important reasons of the surging prevalence of childhood obesity all over the world. Obesity and high fat intake have been revealed to cause premature activation of hypothalamo-pituitary-gonadal axis and central precocious puberty. The onset of puberty is controlled by neuroendocrine mechanisms containing overlapping and interacting gene networks. The latter contains five major transcriptional level hubs, among which the transcriptional factor p53, a well-established tumor suppressor protein, also plays a crucial role in obesity and metabolic disorders. In the current study, we repeated prior observations that high-fat diet advances vaginal opening in rodents and extended these findings by demonstrating that high-fat diet mice had higher expression of p53 in hypothalami than mice fed with normal chow. More importantly, in high-fat diet mice, hypothalamus-specific overexpression of p53 can make vaginal opening much earlier, while inhibition of p53 expression relatively delayed vaginal opening. The c-Myc and Lin28b levels increased, while let-7a mRNA levels decreased in the high-fat diet mice. Overexpression of p53 reduced c-Myc and Lin28b mRNA and protein levels, whereas elevated let-7a mRNA levels in high-fat diet mice. Inhibition of p53 expression by pifithrin-α elevated c-Myc and Lin28b but reduced let-7a levels in high-fat diet mice. In conclusion, high fat intake can accelerate the onset of puberty by up-regulation of p53 expression in hypothalamus. Overexpressed p53 may accelerate hypothalamo-pituitary-gonadal axis activation partially through the c-Myc/Lin28/let-7 system. Impact statement High-fat intake and subsequent obesity are associated with premature onset of puberty, but the exact neuroendocrine mechanisms are still unclear. The transcriptional factor p53 has been predicted to be a central hub of the gene networks controlling the pubertal onset. Besides, p53 also plays crucial roles in metabolism. Here, we explored p53 in the hypothalami of mice fed a high-fat diet (HFD), which showed an up-regulated expression. Besides, we also revealed that overexpressed p53 may accelerate hypothalamo-pituitary-gonadal (HPG) axis activation partially through the c-Myc/Lin28/let-7 system. These results can deepen our understanding of the interaction between metabolic regulation and puberty onset control, and may shed light on the neuroendocrine mechanisms of obesity-related central precocious puberty.