Endocrine Abstracts (2012) 28 P179

Heterozygosity in the leptin receptor gene predisposes to placental and fetal overgrowth

Raja Nadif, Lewis Renshall, Bernadette Baker, Mark Dilworth, Colin Sibley, John Aplin1 & Melissa Westwood

Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom.

Mutations in the leptin receptor gene (Lepr) occur spontaneously in humans and mice and are linked to early onset obesity and diabetes. Mice heterozygous for a signalling-deficient receptor (db/+) are widely used as a model of gestational diabetes that results in fetal macrosomia, but the contribution of the fetal genotype has yet to be evaluated. Eight week old wild type (wt) females (n=8) were mated to db/+ males and db/+ females (n=10) were mated to wt males in order to generate mixed litters. Day of plug was counted as E0.5 and fetal and placental measurements were taken at E18.5. Statistical analysis was performed by Mann-Whitney U test. Regardless of maternal genotype, placentas from db/+ fetuses (n=77) were 5% larger (P<0.05) than those of wt fetuses (n=57). db/+ fetuses born to wt dams (n=35) exhibited a significantly higher (7%) birth weight than their wt littermates (n=27, P=0.01), Similarly, db/+ fetuses born to db/+ mothers (n=42) were significantly bigger (4.5%) than their wt littermates (n=30; P=0.006). Surprisingly, maternal genotype had no effect on progeny birthweight; db/+ pups born to db/+ mothers were of similar size (1086 ± 10.91mg) to those born to wt dams (1090 ± 15.53 mg). Similarly, wt pups born to db/+ mothers were no bigger than if they were born to wt mothers (1039 ± 12.1 mg vs 1017 ± 18.3 mg respectively). Placentas and fetuses heterozygous for the lepr mutation are larger regardless of maternal genotype. It is likely that lepr heterozygosity affects placental leptin production and consequently placental development leading to abnormal fetal growth. Studies using the db/+ mouse to model fetal programming by the maternal environment should be mindful of the genetic predisposition to fetal overgrowth revealed by these experiments.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: Diabetes UK.

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