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.

中文翻译：

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p53 的过表达通过 Lin28/let-7 系统加速高脂饮食喂养小鼠的青春期

高脂肪摄入量是全球儿童肥胖率飙升的最重要原因之一。肥胖和高脂肪摄入已被证实会导致下丘脑-垂体-性腺轴的过早激活和中枢性性早熟。青春期的开始由包含重叠和相互作用基因网络的神经内分泌机制控制。后者包含五个主要的转录水平中心，其中转录因子p53是一种成熟的肿瘤抑制蛋白，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阴道开口，并通过证明高脂肪饮食小鼠具有更高的p53表达来扩展这些发现在下丘脑中比用正常食物喂养的小鼠。更重要的是，在高脂饮食小鼠中，p53 的下丘脑特异性过表达可以使阴道开口更早，而p53表达的抑制相对延迟了阴道开口。在高脂肪饮食小鼠中，c-Myc和Lin28b水平增加，而let-7a mRNA 水平降低。p53 的过表达降低了c-Myc和Lin28b mRNA 和蛋白质水平，而高脂肪饮食小鼠的 let-7a mRNA 水平升高。pifithrin-α 抑制 p53 表达提高了c-Myc和Lin28b但降低了let-7a高脂肪饮食小鼠的水平。总之，高脂肪摄入可以通过上调下丘脑p53 的表达来加速青春期的开始。过度表达的p53可能会部分通过c-Myc/Lin28/let-7系统加速下丘脑-垂体-性腺轴的激活。

影响陈述

高脂肪摄入和随后的肥胖与青春期过早发作有关，但确切的神经内分泌机制仍不清楚。转录因子p53已被预测为控制青春期开始的基因网络的中心枢纽。此外，p53在新陈代谢中也起着至关重要的作用。在这里，我们探索了喂食高脂肪饮食 (HFD) 的小鼠下丘脑中的p53，其表达上调。此外，我们还发现过表达的p53可能部分通过c-Myc/Lin28/let-7加速下丘脑-垂体-性腺 (HPG) 轴的激活系统。这些结果可以加深我们对代谢调节和青春期开始控制之间相互作用的理解，并可能揭示肥胖相关中枢性性早熟的神经内分泌机制。