GENDER-SPECIFIC INFLUENCE OF Aу MUTATION ON PROGENY METABOLIC PHENOTYPE, FETAL GROWTH AND PLACENTAL GENE EXPRESSION IN MICE

Abstract

Obesity during pregnancy increases the risk of obesity in offspring. To correct the offspring development in obese mothers, it is necessary to reveal the molecular mechanisms that mediate the influence of the maternal environment on the offspring ontogenesis. Leptin levels increase with obesity. In C57Bl mice, the Ау mutation is associated with elevated blood levels of leptin in pregnant females and exerts a gender-specific effect on the metabolic phenotype of mature offspring. Aim: to study the influence of Ау mutation on sensitivity to diet-induced obesity in male and female offspring, on fetal and placental weight and on the expression of genes in the placentas of the fetuses of different sexes. Body weight and food intake on a standard and an obesogenic diet, fetal and placental weights on pregnancy days 13 and 18, and gene expression of glucose transporters (GLUT1, GLUT3), neutral amino acid transporters (SNAT1, SNAT2, SNAT4), insulin-like growth factor 2 IGF2 and its receptor IGF2R were measured in male and female offspring of и ɑ/ɑ (control) and Ау/ɑ mothers. Ay mutation influenced the body weight only in male offspring, which consumed a standard diet, and did not influence obesity development in both male and female offspring. The weight of fetuses and placentas in Ау/ɑ as compared to ɑ/ɑ females was reduced on day 13 of pregnancy and was not different on day 18. On day 13 of pregnancy, the mRNA levels of the examined genes did not differ in placentas of male and female fetuses in ɑ/ɑ females. In Ау/ɑ females, the gene expression of GLUT1, GLUT3, SNAT1 and SNAT4 was reduced in female placentas compared to male placentas. The results suggest that the sex-specific transcription response of placentas to elevated leptin levels in pregnant Ау/ɑ females can mediate the gender-specific impact of Ау mutation on the offspring metabolism in postnatal life.

Sex‐specific effects of leptin administration to pregnant mice on the placentae and the metabolic phenotypes of offspring

“…However, in vivo experiments on leptin-treated pregnant mice and rats have shown that maternal leptin inhibits fetal growth [10,32]. Previously, we found that the weights of foetuses in mice with the A y mutation (this mutation increases the blood leptin levels during pregnancy [33]) were lower than those in the control mice on GD13 [34]. Our results are consistent with this previous finding and clearly demonstrate that maternal leptin inhibits fetal growth in mid-pregnancy.…”

“…Interestingly, in A y mice, elevated leptin levels were also associated with a decreased expression of Slc2a1 in the placentas of only female foetuses . Taken together, our results indicate that the elevation of blood leptin levels in mice in mid‐pregnancy sex‐specifically inhibits the expression of gene encoding GLUT1 in placentas.…”

“…According to this assumption, growth inhibition in male and female foetuses was associated with different placental responses to leptin administration as follows: the lowering of placenta weight in male foetuses and the inhibition of Slc2a1 gene expression in placentas of female foetuses. Interestingly, in A y mice, elevated leptin levels were also associated with a decreased expression of Slc2a1 in the placentas of only female foetuses [34]. Taken together, our results indicate that the elevation of blood leptin levels in mice in mid-pregnancy sex-specifically inhibits the expression of gene encoding GLUT1 in placentas.…”

“…same sex-specific differences in placental weight were observed in mice on GD13 [34] and GD18 [35,36], both in other species [37] and in humans [38]. At the same time, the placental expression levels of genes encoding the glucose transporter Slc2a1 (GLUT 1) and the amino acid transporters Slc38a2 (SNAT2) and Slc38a4 (SNAT4) were higher in the female foetuses than the expression levels in the male foetuses.…”

“…The effect of leptin administration on the growth of the foetuses is probably mediated via its influence on placental functions. Earlier in the genetic model, we found that an increased level of leptin in A y mice was accompanied by a decrease in the weights of both the foetuses and the placentas .…”