Leptin responsiveness and gene dosage for leptin receptor mutation (fa) in newborn rats. Am. J. Physiol. 276 (Endocrinol. Metab. 39): E836-E842, 1999.-To determine the degree to which the leptin receptor mutation (fa) influences the responsiveness to leptin during the first postnatal week, we injected recombinant leptin (600 pmol · g Ϫ1 · day Ϫ1 sc from day 1 to day 7) into wild-type (ϩ/ϩ), heterozygous (ϩ/fa), and fatty (fa/fa) rat pups. Growth and final body fat content of these leptin-treated pups were compared with those of saline-treated littermates of the same genotype. The body mass of the leptin-treated ϩ/ϩ pups, but not that of the ϩ/fa and fa/fa pups, increased more slowly than that of their respective controls, and fat content at day 7 was reduced by 37% in ϩ/ϩ pups, by 22% in ϩ/fa pups, but not at all in fa/fa pups. Plasma leptin remained excessively high throughout the day under this treatment, but a 30-fold lower leptin dose, causing only moderate changes of plasma leptin, still reduced the body fat of ϩ/ϩ pups significantly. We conclude that leptin participates in the control of even the earliest stages of fat deposition and that the response to supraphysiological doses of leptin is markedly reduced in 1-wk-old pups with one fa allele and absent in pups with two fa alleles.The body mass of the leptin-treated ϩ/ϩ pups increased more slowly than that of their control litter-E837 LEPTIN RESPONSIVENESS AND RECEPTOR DEFECT IN RAT PUPS