During gestation, adequate nutrient partitioning between mother and fetus is required for optimal maternal and fetal outcomes. The placenta, the barrier between mother and fetus plays a key role in this partitioning; not only by transporting nutrients to support fetal growth, but also by secreting hormones, which alter the maternal metabolism. Disturbances in placental endocrine function may lead to adverse fetal outcomes and pregnancy complications, such as gestational diabetes mellitus (GDM). The Developmental Origins of Health and Disease (DOHaD) theory suggests that adversity in prenatal and early life, influence offspring health. Multiple studies have now shown that the maternal environment (GDM, diet and stress) can affect placental growth, birthweight, and programme the offspring’s risk of long-term health, including increasing risk for metabolic diseases. However, the precise role of the placenta, particularly the role of placental endocrine function, in the developmental programming of offspring metabolic health is unknown.

To study this, Insulin-like Growth Factor 2 (Igf2), known to be important in controlling the formation and function of placental endocrine cells, was conditionally knocked down in the mouse placental endocrine zone (junctional zone, Jz; paternally inherited Jz-Igf2UE). The aims of this study were to; 1) evaluate how Jz-Igf2UE impacts offspring metabolic health, 2) assess the impacts of Jz-Igf2UE on offspring insulin signalling and lipid handling in the liver, skeletal muscle and adipose tissue 3) determine the effect of Jz-Igf2UE on adipose tissue respirometry, and on the gonadal adipose transcriptome. The impact of Jz-Igf2UE on offspring metabolic health was evaluated via insulin tolerance tests, metabolic cage assessments and measuring lean mass and adiposity at multiple timepoints. Insulin signalling and lipid handling in the offspring was assessed by determining the abundance of proteins and mRNAs involved in gluconeogenesis, insulin signalling and lipid metabolism in the liver, skeletal muscle and white adipose tissue, using western blotting and quantitative Polymerase Chain Reactions (qPCR). RNA sequencing and bioinformatic analysis was used to assess changes in gene expression/functional pathways in the adipose tissue, and adipose tissue respirometry was assessed by ex vivo high resolution respirometry. This study showed that Jz-Igf2UE did lead to changes in the metabolic phenotype of the offspring, as indicated by alterations in growth, adiposity, insulin handling, respiratory exchange ratio (RER) and energy expenditure. This was also accompanied by changes in the abundance of proteins and mRNA involved in gluconeogenesis, insulin signalling and lipid metabolism in offspring liver, skeletal muscle and white adipose tissue. However, these alterations were largely dependent on offspring sex and age, with female offspring showing more detrimental metabolic changes than males. These sex-dependent programmed changes in offspring metabolic physiology, in part, may be linked to the sex-specific alterations seen in the adipose tissue transcriptome.

Overall, this study highlights the importance of the placental endocrine function in postnatal offspring metabolic health. Moreover, these placental defects programme sex-specific changes in offspring metabolic physiology as well as sex-specific transcriptome changes in the adipose tissue. By improving our understanding of how placental endocrine malfunction leads to the programming of offspring health, in the future we may consequently improve metabolic disease outcomes associated with developmental origins.