Leptin receptors are expressed in various tissues in rodents but their function is not clear. The present studies were undertaken to investigate the function of the leptin receptor in mouse and human lungs. Cell proliferation, assessed with [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), was significantly less in primary cultures of tracheal epithelial cells of db/db mice than in those of their lean littermates. Mouse recombinant leptin significantly increased cell proliferation only in lean mice, but not in db/db mice. Reverse transcription-polymerase chain reaction (RT-PCR) study demonstrated the existence of a long form, OB-Rb type leptin receptor in both human lung tissue and lung squamous cell line (SQ-5). Cell proliferation, assessed with MTT, was dose-dependently increased in SQ-5 cells incubated with 10-1000 ng/ml human recombinant leptin for 6 h. The 5-bromo-2'-deoxyuridine (BrdU) uptake into SQ-5 cells was also increased by the addition of 10-100 ng/ml human recombinant leptin. Mitogen-activated protein (MAP) kinase activity was significantly increased by 10 and 100 ng/ml human recombinant leptin in SQ-5 cells. MAP kinase kinase (MEK)-1-specific inhibitor, (2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one) (PD98059), blocked the increase in BrdU uptake into SQ-5 cells caused by human recombinant leptin. In conclusion, leptin (OB-Rb) receptors exist in human lung tissue and leptin may have stimulatory effects on the proliferation of cells of a human cell line and mouse tracheal epithelial cells through its specific leptin receptor.