Leptin as a Key Driver for Organ Fibrogenesis

Leptin, a hormone primarily secreted by adipocytes, plays a central role in the regulation of 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, respectively. Leptin neutralization significantly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces local pro-inflammatory and pro-fibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a crucial role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach. Overall design: RNA-seq for the kidneys of mice subjected to folic acid or vehicle treatment, followed by administration of either IgG or leptin antibody after folic acid–induced kidney injury. RNA-seq for the lungs from mice treated with bleomycin or vehicle, followed by IgG (IgGL) or leptin antibody (LepL) administration.