A weight gain of 20-30% above baseline, induced by gastrostomy overfeeding of subhuman primates or gavage overfeeding of rats, was found to completely suppress voluntary food consumption. When overfeeding was discontinued, body weight and oral intake returned in a coordinated fashion to baseline or “set point” values. This regulatory response could have been due to a circulating peptide that was secreted by adipocytes in proportion to the total body energy store and that mediated satiety at the level of the central nervous system. To search for this factor, a subtractive cDNA cloning strategy was developed, permitting the isolation of primate adipocyte genes with augmented expression in the overfed state. A 1.8-kb cDNA clone prepared by subtraction was found to hybridize to a 5-kb message expressed preferentially in the adipose tissue of overfed macaques and rats. This message, which was restricted in distribution among nonadipose tissues, was also detected in human subcutaneous fat. Candidate genes for satiety factors identified by this approach could be used in further studies of body weight regulation and obesity.