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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.

Overexpression of p53 accelerates puberty in high-fat diet–fed mice through Lin28/let-7 system