ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation

Hongling Hu, Sheng Luo, Pinglin Lai, Mingqiang Lai, Linlin Mao, Sheng Zhang, Yuanjun Jiang, Jiaxin Wen, Wu Zhou, Xiaolin Liu, Liang Wang, Minjun Huang, Yanjun Hu, Xiaoyang Zhao, Laixin Xia, Weijie Zhou, Yu Jiang, Zhipeng Zou, Anling Liu*, Bin GuoXiaochun Bai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

Original languageEnglish
Article numbere2310685120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
Publication statusPublished - 2024
Externally publishedYes


  • heterotopic ossification
  • leptin receptor


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