ABNORMAL REGULATION OF THE LEPTIN GENE IN THE PATHOGENESIS OF OBESITY

A subset of obese humans has relatively low plasma levels of leptin, T his finding has suggested that in some cases abnormal regulation of th e leptin gene in adipose tissue is etiologic in the pathogenesis of th e obese state. The possibility that a relative decrease in leptin prod uction can lead to obesity was tested by mating animals carrying a wea kly expressed adipocyte specific aP2-human leptin transgene to C57BL/6 J ob/ob mice (which do not express leptin), The transgene does not con tain 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 trans gene had a plasma leptin level of 1.78 ng/ml, which is approximate to one-half that found in normal, nontransgenic mice (3.72 ng/ml, P < 0.0 1), The ob/ob animals expressing the leptin transgene were markedly ob ese though not as obese as ob/ob mice without the transgene, The infer tility as well as several of the endocrine abnormalities generally evi dent in ob/ob mice were normalized in the ob/ob transgenic mice. Howev er, the ob/ob transgenic mice had an abnormal response when placed at an ambient temperature of 4 degrees C, suggesting that different thres holds exist for the different biologic effects of leptin, Leptin treat ment of the ob/ob transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wild-type mice. In ag gregate these data suggest that dysregulation of leptin gene can resul t in obesity with relatively normal levels of leptin and that this for m of obesity is responsive to leptin treatment.