Leptin-receptor gene expression in hypothalamic tissue from lean and obese humans was examined. The fulllength leptin receptor, that is believed to transmit the leptin signal, is expressed in human hypothalamus. There was no difference in the amount of leptin-receptor mRNA in seven lean (BMI 23.3 ± 0.9 kg/m2) and eight obese (BMI 36.9 ± 1.5) subjects as determined by reverse transcription-polymerase chain reaction. A sequence polymorphism (A→G) was detected at position 668 of the leptin receptor cDNA. This second base substitution changed a glutamine to an arginine at position 223 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. The occurance of the polymorphic allele(s) did not correlate with BMI in the population studied. The mutation responsible for the defect in the leptin receptor in db/db mice was not detected in any obese human, nor was the fa/fa rat mutation. These results provide evidence that the leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

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