A subset of obese humans has relatively low plasma levels of leptin. This finding has suggested that in some cases abnormal regulation of the leptin gene in adipose tissue is etiologic in the pathogenesis of the obese state. The possibility that a relative decrease in leptin production can lead to obesity was tested by mating animals carrying a weakly expressed adipocyte specific aP2-human leptin transgene to C57BL/6J ob/ob mice (which do not express leptin). The transgene does not contain the regulatory elements of the leptin gene and is analogous to a circumstance in which the cis elements and/or trans factors regulating leptin RNA production are abnormal. The ob/ob mice carrying the transgene had a plasma leptin level of 1.78 ng/ml, which is ≈one-half that found in normal, nontransgenic mice (3.72 ng/ml, P < 0.01). The ob/ob animals expressing the leptin transgene were markedly obese though not as obese as ob/ob mice without the transgene. The infertility as well as several of the endocrine abnormalities generally evident in ob/ob mice were normalized in the ob/ob transgenic mice. However, the ob/ob transgenic mice had an abnormal response when placed at an ambient temperature of 4°C, suggesting that different thresholds exist for the different biologic effects of leptin. Leptin treatment of the ob/ob transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wild-type mice. In aggregate these data suggest that dysregulation of leptin gene can result in obesity with relatively normal levels of leptin and that this form of obesity is responsive to leptin treatment.