Pro-opiomelanocortin (POMC)-derived peptides play a critical role in body weight regulation in the central nervous system. Mice deficient in POMC developed obesity. We sought mutations in the POMC gene in 50 morbidly obese (body mass index 35-60 kg/m(2)) Japanese subjects with diabetes by direct sequencing. Apart from two silent mutations (C6982T and C7285T), no other mutations were detected. Frequencies of these mutations were not significantly different between 100 obese subjects and 100 controls. Also, the frequencies did not differ in the subjects with or without diabetes. These results suggest that mutations in the POMC gene are unlikely to be a major factor of obesity or diabetes in Japanese subjects.