Random mutations in inbred mice exhibited 5 mutant loci with major obesity phenotypes. Two of these are ob (obese) and db (diabetes, diabetes is very common in obese mice and humans). Coupling the circulatory system of a normal mouse to an ob/ob mouse caused both mice to be normal, suggesting that a circulating hormone was lacking in ob/ob mice. Coupling a db/db mouse to a normal or ob/ob mouse did not change the db/db mouse, suggesting that the defective molecule in db/db mice does not circulate. (In trying to compensate for their problem, db/db mice overproduce the ob hormone, thereby reducing the weight of their coupled partner.) Since the phenotypes of ob/ob and db/db were virtually identical, this suggests that the db-defective molecule could be the receptor for the ob-defective hormone.
Friedman's group at Rockefeller used genetic map-based cloning to isolate the ob-defective gene and showed that this gene did encode a protein hormone called leptin. Tartaglia's group at Millenium Pharmaceuticals isolated the gene for the ob receptor, Ob-R, and showed (along with Friedman) that a particular form of the Ob-R protein is defective, as predicted, in db/db mice. This specific form of Ob-R is primarily made in the hypothalamus in the brain, the probable site of leptin action.
Fatty tissues in the body make leptin, the more fat, the more leptin. Leptin goes to the hypothalamus and binds Ob-R (Ob-R is a cytokine-type receptor which activates a transcription factor called STAT3). It is believed that leptin binding may trigger a decrease in the amount of neuropeptide Y that is made. (At least two other previously-identified mutant genes, tubby and fat, may be involved in the synthesis of neuropeptide Y in the hypothalamus.) Neuropeptide Y is believed to migrate to another region of the hypothalamus. Among the effects of neuropeptide Y is an increase in feeding.