Hyperleptinemia and leptin receptor variant Asp600Asn in the obese, hyperinsulinemic KK mouse strain

KK obese mice exhibit a multigenic syndrome of moderate obesity, hyperinsul inemia and hyperglycemia. Here we show that the syndrome is accompanied by a marked elevation of leptin protein in adipose tissue, as well as leptin l evels in serum, which corresponds with the degree of obesity. The cDNA sequ ence of leptin is normal in KK mice, whereas three nucleotide polymorphisms were found in the cDNA of the leptin receptor, one of them resulting in ex change of an aspartate residue for asparagine (Asp600Asn) in a highly conse rved part of the second extracellular cytokine-receptor homology module. In female (but not male) F2 mice of a C57BL/6J x KK intercross, the weight of gonadal, retroperitoneal and mesenteric adipose tissue was positively corr elated with the number of alleles inherited from the KK parental strain at a microsatellite marker (D4Mitl 75) which maps close (0.7 centimorgan proxi mal) to the leptin receptor gene. It is suggested that the Asp600Asn leptin receptor variant contributes to the obesity syndrome in KK female mice, bu t that its contribution is only a part of the multigenic syndrome.