Muricholic acid mediates puberty initiation via the hypothalamic TGR5 signaling pathway
Abstract
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 induced premature sexual development in female mice. Mechanistically, we demonstrated that MCA had strong activation effects on Takeda G-protein-coupled receptor 5 (TGR5), and MCA enhanced GnRH expression in GnRH neurons through activation of the TGR5-PI3K/Akt-mTOR signaling pathway. Our findings reveal a link between metabolic status and reproductive maturation, highlighting MCA as a potential therapeutic target for managing early puberty initiation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Shan Wang
Ministry of Education Key Laboratory of Cluster Science, Frontiers Science Center for High Energy Material, School of Interdisciplinary Science, School of Chemistry and Chemical Engineering
Ke Huang
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Ana Liu
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Senjie Wang
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Runqiu Jiang
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School
Wenlian Chen
Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine
Huiying Wang
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Rahim Ullah
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Chuqing Xue
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Wei Wu
Guanping Dong
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Peifang Jiang
Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Junfen Fu
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Yan Ni
Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health