What is it about?
The onset of puberty is increasingly observed at earlier ages in children, especially in girls with obesity, a trend that predisposes them to long-term metabolic and reproductive disorders in adulthood. Bile acids have emerged as pivotal signaling molecules in both metabolic and reproductive disorders, but remain unexplored in the early onset of puberty in children. Herein, we find elevated levels of muricholic acid (MCA) species in the serum of girls with central precocious puberty, which strongly correlate with indices of hypothalamic-pituitary-gonadal axis activation and can reach peak levels during puberty among healthy children. Intriguingly, reduction of MCA species can lead to decreased expression of gonadotropin-releasing hormone (GnRH) and delay the early onset of puberty, while elevated MCA levels were demonstrated to causally induce premature sexual development in female mice. Mechanistically, we demonstrate that MCA had strong activation effects on TGR5, and MCA enhance GnRH expression in GnRH neurons through activation of TGR5-PI3K/Akt-mTOR signaling pathway. Our findings reveal a novel link between metabolic status and reproductive maturation, highlighting MCA as a potential therapeutic target for managing early puberty initiation.
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Why is it important?
Considering central precocious puberty as a metabolic disorder, we employed a metabolomics approach to profile bile acids—a class of small molecules increasingly recognized as crucial signaling agents in metabolic and reproductive health. Our analysis revealed muricholic acid species as novel biomarkers. This discovery significantly expands the understanding of bile acids' biological functions, suggesting their involvement in the initiation of sexual development.
Perspectives
Central precocious puberty (CPP), triggered by the early activation of the hypothalamic-pituitary-gonadal (HPG) axis, poses several unresolved clinical problems. Girls are affected far more frequently than boys (5-10 times) and confront an increased lifetime risk of conditions like PCOS, breast cancer, and cardiovascular disease. Diagnosing CPP remains a hurdle, as the gold-standard GnRH stimulation test is painful and time-consuming due to serial blood collections. Compounding this issue, the necessary medical treatments are costly and typically not covered by health insurance, creating a significant financial strain for many families. Our findings, which reveal novel metabolic mechanisms and potential biomarkers, offer a promising avenue for developing more accessible and efficient strategies for CPP management.
Yan Ni
Zhejiang University
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This page is a summary of: Muricholic acid mediates puberty initiation via the hypothalamic TGR5 signaling pathway, Proceedings of the National Academy of Sciences, September 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2511404122.
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