Leptin as a key driver for organ fibrogenesis
Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting the kidney, liver, lung, heart, and blood vessels. Leptin neutralization markedly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces pro-inflammatory and profibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a vital role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach.
Authors
- Giovanna Rosa Degasperi (ORCID: https://orcid.org/0000-0002-0317-2532)
- Chanmin Joung (ORCID: https://orcid.org/0000-0003-0004-3441)
- Diana R. Tomchick (ORCID: https://orcid.org/0000-0002-7529-4643)
- Lisandro Maya-Ramos (ORCID: https://orcid.org/0000-0002-4424-7537)
- Zhiqiang An (ORCID: https://orcid.org/0000-0001-9309-2335)
- Lilian Pedersen (ORCID: https://orcid.org/0000-0003-1002-4009)
- Qian Lin
- Richard Wynn (ORCID: https://orcid.org/0000-0002-1879-2136)
- Dayoung Oh (ORCID: https://orcid.org/0000-0003-0687-6479)
- Jan‐Bernd Funcke (ORCID: https://orcid.org/0000-0002-2596-3167)
- Ayanna Cobb
- Kyounghee Min (ORCID: https://orcid.org/0000-0002-2546-0236)
- Philipp E. Scherer (ORCID: https://orcid.org/0000-0003-0680-3392)
- Junquan Liu (ORCID: https://orcid.org/0000-0002-0166-164X)
- Shiuhwei Chen
- Shangang Zhao (ORCID: https://orcid.org/0000-0002-9209-8206)
- Ningyan Zhang (ORCID: https://orcid.org/0000-0002-4348-2180)
- Chao Li (ORCID: https://orcid.org/0000-0002-2060-4835)
- Yan Li (ORCID: https://orcid.org/0000-0002-3077-8097)
- Xue-Nan Sun
- May-Yun Wang
- Megan Virostek (ORCID: https://orcid.org/0009-0005-4968-2529)
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- Brown Foundation (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1126/sciadv.ady7904
- Citations
- 2
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 1.83