Role of obesity and gestational diabetes mellitus status on the expression of kisspeptin, inflammatory markers and other endocrine signals, and their correlation with foetal outcomes and placental structure

Musa, Ezekiel

Role of obesity and gestational diabetes mellitus status on the expression of kisspeptin, inflammatory markers and other endocrine signals, and their correlation with foetal outcomes and placental structure

Doctoral Thesis

2022

Abstract

Background: Maternal obesity and gestational diabetes mellitus (GDM) are associated with short and long-term health risks for the mother and child. The placenta produces hormones, including steroids and cytokines, that influence maternal glucose control. Current literature links kisspeptins with glucose-stimulated insulin secretion, and low plasma kisspeptin concentrations have been associated with GDM and markers of insulin resistance. In addition, maternal obesity is characterized by low-grade inflammation and insulin resistance. However, little is known about the effect of maternal obesity and GDM and their interaction on placental kisspeptin and inflammatory marker (TNFα, IL-6) expression, the relationship between placental and circulatory kisspeptin and inflammatory markers with placental villous morphology and maternal and neonatal parameters. There is also a paucity of data on the effect of maternal obesity and GDM on other endocrine signals (leptin, placental lactogen family members), growth factors (IGF2, VEGF), and steroidogenic hormone enzyme gene expression in the placenta. Aim: This work aimed to examine the effect of maternal obesity and/or GDM on molecular expression (placental, maternal and cord serum) of kisspeptin and inflammatory markers (TNFα, IL-6) and placental morphology, and how these effects relate to maternal and neonatal clinical parameters. Additionally, the work aimed to investigate the effect of maternal obesity and/or GDM on leptin, placental lactogen family members, growth factors, and steroidogenic hormone enzymes gene expression in the placenta. Methods: This study included 4 groups of South African pregnant women: Non-GDM, Non-obese (n=14); Non-GDM, Obese (n=19); GDM, Non-obese (n=15); GDM-Obese (n=23). At delivery, the women's placental tissue was fixed and processed for immunohistochemistry and histological assessment as well as snap-frozen for RT-qPCR and Western Blot analysis. Maternal and cord blood were also collected for the measurement of placenta-derived factors by ELISA. Data were compared by two-way ANOVA with Bonferroni multiple comparisons tests. Results: Maternal obesity and GDM had no effect on placental kisspeptin gene and protein expression, immunostaining or circulatory levels. There was a significant negative correlation between placental kisspeptin gene expression and volume of villous syncytiotrophoblasts and theoretical diffusion capacity in non-obese women irrespective of their GDM status. There was a significant inverse correlation between plasma kisspeptin protein and BMI and maternal systolic blood pressure in GDM women regardless of obesity. Cord serum kisspeptin concentration correlated negatively with BMI. Maternal obesity reduced placental Leptin and KISS1R gene expression in the absence of GDM. Overall, placental TNFα protein abundance by immunostaining was significantly higher in women with obesity irrespective of GDM status. TNFα staining of terminal villi syncytiotrophoblast was increased in women with obesity, while IL-6 staining of terminal villi stroma and foetal vessels was reduced in obese women, significantly so in GDM women. There was a positive correlation between the expression of placental TNFα gene and IL6 protein and maternal diastolic blood pressure in obese non-GDM and GDM women, respectively. In obese non-GDM women, maternal serum TNFα and IL-6 concentrations correlated negatively with placenta weight, foetoplacental ratio and volume of intervillous space, and theoretical and specific diffusion capacity, respectively. Women with obesity showed fewer terminal villi with fewer syncytiotrophoblast, foetal vessels and stroma dependent on GDM diagnosis while GDM influenced intervillous space volume by increasing it in obese groups. Maternal obesity also affected the surface areas for maternal-foetal exchange; the surface area of maternal blood space and foetal capillary were reduced in women with obesity regardless of GDM status. Again, the physiological diffusion gradients for oxygen transfer at the maternal-foetal interface were significantly reduced by maternal obesity. Conclusion: This study shows neither maternal obesity nor GDM influences kisspeptin levels, although maternal obesity in the absence of GDM seems to downregulate KISS1R, which may impact the kisspeptin-KISS1R signalling pathway. GDM rather than obesity may have a greater effect on TNF-α mediated maternal circulatory and placental inflammation. This study suggests that placental inflammation and insulin resistance may have a relationship with hypertension. In obese women alone, maternal inflammatory cytokines seem to be associated with altered placental structure and function. Indeed, maternal obesity was shown to compromise placental maturation and decrease the surface area and diffusion capacity required for maternal-foetal nutrient and oxygen exchange. These observations are likely to contribute novel insights into the interplay between metabolic dysfunction, obesity, and inflammation in the pathophysiology of GDM and placental dysfunction.

Keywords

Medicine

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PhD / Doctoral

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