Resumen de Effect of maternal obesity and gestational diabetes on placental fatty acid uptake, metabolism and transfer to the fetus
The prevalence of obesity has triplicate by the last thirty years, reaching the magnitude of epidemic. Recent data from the World Health Organization are alarming. Approximately the 40% and the 15% of women older than 18 years are overweight and obese, respectively. Specially worrying are data in respect infant and young population. From 1975 to 2016 the prevalence of overweight and obesity has increase to 18%, the worldwide prevalence of infant and teenager is about 8%.
Obesity must be considered as a complex multifactorial disorder resulting of the interaction of several environmental and genetic factors. Changes in dietary and physical activity patterns associated to social changes are disturbing especially in children and adolescent Regardless of the cause, obesity represent an important global health concern. Excessive fat accumulation has been found to be a major risk factor for the four group of noncommunicable diseases: cardiovascular diseases, diabetes, musculoskeletal disorders and some kinds of cancer.
Obesity is specially worrying in women of reproductive age. Women with excessive body weight/fat accumulation at conception face many obstetric complications such as miscarriage, gestational hypertension, preeclampsia, gestational diabetes and cesarean delivery. In addition, offspring from obese women are in major risk of macrosomia, neural tube defects, and congenital heath disease. Furthermore, nutritional milieu associated to maternal obesity increases the risk of metabolic complications later in their descendance. For first time, Barker et al. linked an unfavorable environment during pregnancy with the origin of diseases in adult life. Some maternal metabolic pathologies, such as obesity and gestational diabetes, are associated to an unfavorable nutritional status. Maternal malnutrition includes both excess and deficit of nutrients. Thus, offspring born from obese or diabetic mother shown increased insulin resistance, adiposity, and higher risk to develop metabolic syndrome later in life.
Although mechanism involved in early programming of health and disease remains unclear, the placenta may play an important role on the long-term consequences of maternal complications during pregnancy. Maternal pathologies may compromise the placental morphology and function, altering its nutrient transport capacity, and creating an unfavorable intrauterine environment for the developing fetus.
During pregnancy, maternal metabolism changes to adapt to the nutritional fetal requirements. Those changes are mediated by maternal and placental hormones. One of the biggest changes that pregnant women experience is in lipid metabolism. At the beginning of gestation, the level of estrogens, progesterone, insulin, and adipose tissue LPL activity increase which favor deposition of fat in maternal tissues. As pregnancy progress, maternal metabolism shift from anabolic to catabolic status. Hence, there are an increase of lipolysis, maternal fat mobilization, and insulin resistant condition. Consequently, the levels of triglycerides and cholesterol increase in maternal blood. The hyperlipidemia found in the third trimester of pregnancy overlap with the period of greatest fetal growth.
The insulin resistant condition is a physiological adaptation in normal pregnancies. This condition may result exacerbated in obese pregnant women, as obesity per se is a state of decreased insulin sensitivity. Furthermore, in some situation the maternal pancreas is unable to produce enough insulin to compensate such resistance, so gestational diabetes is developed. Thus, in those maternal conditions a higher increase of lipids in blood is expected.
Fatty acids play a key role to maintain the well-being and are essential for fetal development. The role of fatty acids in the human body can be classified as metabolic, functional and regulatory. For instance, fatty acids are incorporated in membranes of fetal structures, are precursors of regulatory molecules, and they provide energy substrate. Furthermore, due to their chemical structure long chain polyunsaturated fatty acids are essential for fetal nervous system development.
The fetus can synthesize saturated and short chain monounsaturated fatty acids, but for long chain fatty acids is dependent of maternal supply by the placenta. The placental transfer of essential fatty acids is a complex process mediated by transport and binding proteins, though exact mechanisms remains a matter of discussion.
The placental can protect the fetus from excess or deficit of nutrients. In some metabolic conditions, such as obesity and gestational diabetes, the duration of intrauterine insult may exceed the ability of the placental to adapt, which may alter the supply of nutrients to the fetus, especially fatty acids, with negative consequences for fetal structures development. For instance, the deficiency of long chain polyunsaturated fatty acids, such as DHA and ARA, during gestation and first months of life has been associated with visual defects and cognitive problems in infants.
The general aim of this Doctoral Thesis was to investigate the potential effect of high pre-pregnancy body mass index and gestational diabetes on placental fatty acid content and expression of genes encoding for fatty acid metabolism and transport through the placenta (FATP: fatty acid transport protein, FABP: fatty acid binding protein, FAT/CD36: fatty acid translocase, EL: endothelial lipase and LPL: lipoprotein lipase).
In the present study placentas samples obtained within the PREOBE study were analyzed. The PREOBE study was designed as a prospective observational cohort study. Participant pregnant women were classified at study entry according to their body mass index and glucose tolerance during pregnancy. Thus, women were classified as normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI <30 kg/m2), obese (BMI ≥30 kg/m2), and women with gestational diabetes. To evaluate the effect of gestational diabetes on placenta alone, without the combination of obesity, only normal weight diabetic women were included in this work.
Data from pregnancy and delivery were collected throughout the study. Maternal venous blood and fetal anthropometric measurements by ultrasound were collected at study visits performed at 24 and 34 weeks of gestation. At delivery, maternal and cord venous blood, and placental tissue were collected. Biochemical parameters were determined in serum samples. Placental samples were kept at -80º until their analysis. Fatty acids were quantified by gas chromatography form one piece of placental tissue. A second sample of placenta tissue was used for gene expression analysis by RT- PCR.
Our results showed that maternal excessive pre-conceptional body mass index and gestational diabetes alter the expression of key genes involved in the uptake, metabolism and transfer of fatty acids through the placenta. Moreover, the specific fatty acid composition was different in placentas from the studied group (overweight, obese and gestational diabetic) compared to normal weight ones, while total fatty composition resulted unchanged. The percentage of the total saturated fatty acids in placentas from obese and gestational diabetes women was lower than the percentages found in placentas from healthy weight women, while the percentage of total long chain polyunsaturated fatty acids showed the opposite trend.
The placental surface express receptors for different molecules and hormones, which suggest that the placenta acts as nutritional sensor. Thus, the placenta regulates nutrient supply according to signals generated in both maternal and fetal sides. In this way, when negative stimulus are generated the placenta may activate compensatory mechanisms to modify its nutrient transfer capacity. The observed changes in gene expression of FATP1, FAPT4 and EL may represent a protective mechanism to limit the excess of nutrient supplied to the fetus.
Interestingly, changes in FATPs expression were similar among studied groups while it was not the situation of FABP gene expression. The gene expression of FABP4 was lower in placentas from overweight and obese women compared to those from healthy weight women, while it was unchanged in placentas from gestational diabetic women. The differences observed in placental FABP4 mRNA expression between obese mothers and GDM suggest a differential regulatory pathway for placental FA handling and metabolism in both maternal conditions.
Some authors have reported an increase in levels of triglycerides and cholesterol in maternal plasma at third trimester of pregnancy. Such differences were no found in our population, but trend was higher in both groups. The percentage of glycosylate hemoglobin was higher in blood of overweight, obese and diabetic mother that in blood from normal weight women during pregnancy. Furthermore, a positive correlation was found between the percentage of glycosylated hemoglobin in maternal blood and ultrasound markers of fetal adiposity. Fetus from obese women showed higher markers of adiposity at 24 and 34 weeks of gestation, while fetus from diabetic women showed only at 34 weeks. Our data suggest that intrauterine insult to exacerbated glucose levels begins before second trimester of gestation in obese pregnancies.
Our work is the first to study placental expression of genes involved in lipid transport and metabolism in overweight pregnancies. Interestingly, gene expression in overweight group was like the placental expression from obese mothers, while fatty acid content was more similar to placentas from healthy women. Thus, overweight seems to be an intermediate group between normal weight and obese pregnant women in terms of metabolic disruption. The clinical characteristics of fetal and offspring represent an intermediate situation between normal weight and obesity as well. Fetal adiposity was higher at mid gestation, but it seems that compensatory mechanism activated during last part of gestation were enough to achieve a good fetal adipose tissue development at the end of pregnancy.
During pregnancy, the placenta must integrate nutritional and endocrine signals produced at both maternal and fetal side. Those signals may be sometimes contradictories. For instance, while circulating maternal levels may indicate a good nutritional status, which lead to increased supply of nutrients, regulatory factors produced by fetal tissues may lead to the opposite placental response. Although placental modifications found in our study seem to be a response to protect and maintain the fetal health, the effect of these changes on fetal early programming and consequences in adult life are not yet clear.
