Leptin From Fibro‐Adipogenic Progenitor Cells (FAPs) Regulates Masseter Muscle Disuse Atrophy and Ectopic Fat Accumulation

ABSTRACT Background Excessive fat accumulation in muscles with disuse atrophy may impair muscle physiologic function and exacerbate the progression of atrophy, with causes largely unexplored. Evidence indicates leptin plays a crucial role in regulating skeletal muscle fat metabolism. Masticatory muscle (a special skeletal muscle) atrophy often causes aesthetic and functional problems due to various occlusal factors. This study examines leptin's role and mechanism in masseter muscle disuse atrophy and explores leptin's source. Methods A C57BL/6J mouse disuse atrophy model was established. The ameliorative role of leptin in masseter muscle lipid accumulation and atrophy and its local sources were explored by injection of exogenous leptin and nilotinib, which specifically induces leptin‐producing fibro‐adipogenic progenitor cells (FAPs). Transcriptomic sequencing revealed the molecular mechanism of lipid accumulation in the masseter muscle, which was validated by in vitro experiments. Results Mice with masseter muscle disuse atrophy showed significant fat accumulation (triglycerides, TG: 3.750‐fold elevation, p  < 0.001). Local leptin injection reduced masseter muscle fat accumulation (TG: 2.330‐fold reduction, p  < 0.001) and atrophy index (MuRF‐1: 2.068‐fold reduction, p  < 0.05). Transcriptomic analysis revealed downregulated PPAR lipid metabolism pathways, with significant repression of peroxisome proliferator‐activated receptor α (PPARα) and consequent phenotypic effects. Leptin significantly upregulated PPARα expression (mRNA: 10.814‐fold elevation, p  < 0.001; protein: 1.843‐fold elevation, p  < 0.001). PPARα silencing in C2C12 cells abrogated leptin's lipid‐lowering effect (TG: 3.903‐fold reduction abolished, p  < 0.01). Fluorescence‐activated cell sorting (FACS)‐isolated FAPs expressed leptin mRNA. Nilotinib‐induced FAP apoptosis reduced local leptin expression (1.628‐fold reduction, p  < 0.05) and exacerbated masseter muscle lipid accumulation and atrophy (MuRF‐1: 2.007‐fold elevation, p  < 0.001). Conclusion Disuse atrophy reduces leptin secreted by FAPs, triggering lipid accumulation that exacerbates muscle degeneration. This reveals the critical regulatory role of FAPs in maintaining masseter muscle homeostasis through leptin‐mediated mechanisms.