MUTATIONS in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity(1), Previous data suggest that the db gene encodes the receptor for the obese (ob) gene product, leptin(2-7). A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db(8). This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice, The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.