Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

Background: Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of preexisting cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. Methods: Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction. Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq data sets and histological examination. Results: In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the LepR (leptin receptor). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After myocardial infarction, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. Conclusions: These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.