LEPR (leptin receptor) is a cell surface cytokine receptor that mediates leptin signaling through STAT-dependent pathways, playing a central role in energy homeostasis and glucose regulation. The receptor binds leptin, an adipokine secreted by adipose tissue and placenta, to transduce signals regulating feeding behavior, body weight, and metabolic adaptation 1. Beyond metabolism, LEPR activation orchestrates diverse physiological responses including neuroendocrine function, immune regulation, bone development, and hematopoiesis 12. Recent evidence reveals that LEPR-expressing sympathetic perineurial barrier cells in brown adipose tissue produce interleukin-33, creating an immunomodulatory microenvironment essential for thermogenesis and leptin-mediated metabolic rescue 3. Functionally, LEPR antagonizes leptin endocytosis, regulating the duration of signaling. Biallelic LEPR mutations cause severe monogenic obesity responsive to MC4R agonists, whereas monoallelic variants do not significantly elevate obesity risk 45. Epigenetic alterations in LEPR methylation associate with childhood obesity in a race-specific manner 6. Additionally, LEPR is implicated in colorectal cancer progression and prognosis, suggesting roles beyond metabolic homeostasis 7.