The Leptin receptor (Leptin R; gene name LEPR), also called OB R (obesity receptor), is a 150 kDa protein that is a member of the Class I cytokine receptor family. It mediates the activities of Leptin, a multi-functional hormone produced primarily by adipose tissues that plays roles in food intake, energy metabolism, angiogenesis, reproduction, hematopoiesis, bone metabolism, and immune function (1‑3). The mouse Leptin R gene encodes 1162 amino acids (aa) including a signal peptide, an extracellular region with cytokine receptor homology (CRH), multiple fibronectin type III domains and a WSXWS motif, a transmembrane domain, and a cytoplasmic domain that supports JAK/STAT signaling (2, 3). Mouse Leptin R shares 93% aa sequence identity with rat Leptin R and 74‑76% with human, bovine, canine, equine and porcine Leptin R. Leptin R isoforms include a long form, OB RL or OB Rb (primary signaling form), and at least four shorter isoforms with truncated cytoplasmic domains, named OB Ra (ubiquitous), Rc, Rd, and Rf (2, 4). A soluble isoform, OB Re, is found in rodents but not humans (5). However, both rodents and humans produce soluble Leptin R due to release of soluble ectodomains by metalloproteinases such as ADAM10 (5, 6). OB Rb is highly expressed in the hypothalamus and mediates the anti‑orexigenic effects of Leptin (1, 2). Mutations of ObRb have caused extreme obesity in humans, mice (db/db “diabetes”), and rats (Zucker fa/fa “fatty”) (1, 7‑9). Shorter isoforms of Leptin R exhibit limited signaling capability, but mediate endocytosis and degradation of Leptin and passage through the blood-brain barrier (4, 5, 10, 11). Soluble Leptin R is the primary Leptin‑binding protein in blood, where it maintains a pool of available bioactive Leptin, delays Leptin clearance from circulation, and down‑regulates blood‑brain transmission of Leptin (5‑7, 10). In humans, soluble Leptin R levels are inversely proportional to adiposity and are elevated in females versus males (12). Soluble Leptin R is also found up‑regulated in patients with chronic heart failure, end-stage renal disease, and anorexia (13‑15). It is expressed by tumor‑initiating stem cells, and is proposed as a link between between cancer and obesity (16).