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

Abstract

Obesity during pregnancy has been shown to increase the risk of metabolic diseases in the offspring. However, the factors within the maternal milieu which affect offspring phenotypes and the underlying mechanisms remain unknown. The adipocyte hormone leptin plays a key role in regulating energy homeostasis and is known to participate in sex‐specific developmental programming. To examine the action of leptin on fetal growth, placental gene expression and postnatal offspring metabolism, we injected C57BL mice with leptin or saline on gestational day 12 and then measured body weights (BWs) of offspring fed on a standard or obesogenic diet, as well as mRNA expression levels of insulin‐like growth factors and glucose and amino acid transporters. Male and female offspring born to leptin‐treated mothers exhibited growth retardation before and a growth surge after weaning. Mature male offspring, but not female offspring, exhibited increased BWs on a standard diet. Leptin administration prevented the development of hyperglycaemia in the obese offspring of both sexes. The placentas of the male and female foetuses differed in size and gene expression, and leptin injection decreased the fetal weights of both sexes, the placental weights of the male foetuses and placental gene expression of the GLUT1 glucose transporter in female foetuses. The data suggest that mid‐pregnancy is an ontogenetic window for the sex‐specific programming effects of leptin, and these effects may be exerted via fetal sex‐specific placental responses to leptin administration.

Influence of leptin administration to pregnant female mice on obesity development, taste preferences, and gene expression in the liver and muscles of their male and female offspring

“…Inf luence of leptin administration to pregnant mice on liver weight and blood biochemistry in male and female offspring fed on the obesogenic diet Earlier we found that a single leptin administration to mice on pregnancy day 12 exerts sex-specific programming action on metabolism in the offspring (Denisova et al, 2020). Thus, females are sensitive to leptin in this period, as evident from lower food consumption in response to leptin.…”

“…Leptin, a hormone produced in the adipose tissue, is considered to be a programming factor of the maternal environment. Model experiments indicate that high maternal leptin levels in the pregnancy reduce body weight, increase insulin sensitivity, and improve metabolic characteristics in the adult offspring fed on balanced or high-calorie diets, and this effect may manifest differently in different sexes (Pennington et al, 2012;Makarova et al, 2013;Pollok et al, 2015;Talton et al, 2016;Denisova et al, 2020). Nevertheless, molecular mechanisms mediating the programming action of maternal leptin remain obscure.…”

Fetal Brain Elicits Sexually Conflicting Transcriptional Response to the Ablation of Uterine Forkhead Box A2 (Foxa2) in Mice

“…In rodents, the placenta develops at a relative faster rate in males compared to females [ 13 ]. Relationships between fetal sex and placental functions have been demonstrated in many studies [ 14 , 15 , 16 , 17 , 18 , 19 ]. Recent study shows that uterine Foxa2 influences the growth of fetus and placenta in a sexual dimorphic manner [ 20 ].…”

Placental microRNA expression associates with birthweight through control of adipokines: results from two independent cohorts

“…However through the placental expression of adiponectin receptors, maternal adiponectin might limit fetal growth by inhibiting the production of placental lactogen, chorion gonadotropin and progesterone in trophoblast cells 52,53 . Both of these hormones have been linked to gestational diseases like preeclampsia [54][55][56][57][58] , gestational diabetes [58][59][60][61] and fetal outcomes like intrauterine growth restriction 46,58,59,[62][63][64][65][66] . While earlier work did find positive associations between placental leptin expression and birthweight 59,60,67 , several studies since have found a negative correlation -which is in line with our findings 63,65,[68][69][70][71][72] .…”