Obesity, which was recognised as a chronic disease in 1997, has continued to increase in recent decades. Currently, approximately one third of the world's population is overweight or obese. In addition, obesity is considered a risk factor for other non-communicable diseases such as hypertension, insulin resistance, type 2 diabetes mellitus, dyslipidemia, atherosclerosis, cardiovascular disease and non-alcoholic fat, all of which contribute to compromised cardiometabolic health and poorer quality of life. At the same time, the increase in the prevalence of childhood obesity is also a cause for concern in the medical community, as it is closely related to the onset of other cardiometabolic
cardiometabolic diseases that can persist into adulthood. Exposure to excessive weight gain during pregnancy is associated with complications during pregnancy, such as an increased risk of developing gestational diabetes, preeclampsia, placental dysfunction or alterations in foetal growth and development. In addition, it can also have long-term consequences in terms of influencing cardiac and
cardiometabolic health of the offspring. Evidence from historical events such as the famines supports the idea that stimuli received during gestation may influence a greater susceptibility to develop long-term diseases through foetal programming. The placenta, a temporary organ with the sole function of sustaining the pregnancy and providing oxygen and nutrients to the foetus, integrates the stimuli received during gestation. Using the placenta as a "proxy" of the intrauterine environment could provide biomarkers related to obesity and cardiometabolic risk in the offspring. In this thesis, analysis of the placental lipid profile provides evidence on the relative abundance of placental fatty acids in women from the general population, where polyunsaturated fatty acids (PUFAs) represent
of the total composition. The importance of the PUFA n-6/n-3 ratio in metabolic health is evidenced by the associations found between the AA/EPA ratio (15/1) and cardiometabolic risk parameters in the six-year age range. For example, weight-SDS, BMI-SDS, percentage of fat mass-SDS, visceral fat and HOMA-IR. L'estudi del transport placentari de PUFAs a partir de l'expressió combinada de les proteïnes transportadores d'àcids grassos (FATPs, per les sigles en anglès) FATP-1 i FATP-4 (∑FATPs), revela associacions més robustes entre la ràtio AA/EPA i els paràmetres de risc cardiometabòlic de la descendència dins del grup amb una major expressió relativa de FATPs placentaris (∑FATPs > percentil 50). Així mateix, aquest grup inclou les mares que van experimentar un major augment de pes durant l'embaràs. L'augment de pes excessiu durant l'embaràs s'associa amb la metilació diferencial de 104 dinucleòtids citosina guanina (CpGs), que anoten per a 97 gens. Entre aquests, 4 CpGs que anoten per a 3 gens (FRAT1, SNX5 i KCNK3), mostren associacions significatives amb paràmetres cardiometabòlics de la descendència als 6 anys, entre els quals el Δ BW-SDS - BMI-SDS, el pes-SDS, l'IMC-SDS, la relació cintura-alçada, el greix visceral i el greix renal, ja sigui a nivell de metilació de l'ADN o de transcripció gènica.
En resum, aquesta tesi destaca la importància de la placenta en la integració d’estímuls materns durant la gestació i el seu potencial impacte en la programació del risc cardiometabòlic de la descendència; així com també identifica marcadors placentaris (perfil lipídic i marques de metilació de l'ADN) que es podrien utilitzar com a biomarcadors per predir aquells nens i nenes amb més risc de desenvolupar obesitat i
alteracions cardiometabòliques.The study of placental transport of PUFAs from the combined expression of the fatty acid transporter proteins (FATPs) FATP-1 and FATP-4 (∑FATPs), reveals stronger associations between the AA/EPA ratio and the cardiometabolic risk parameters of the offspring in the group with a higher relative expression of placental FATPs (∑FATPs > 50th percentile). Likewise, this group includes mothers who experienced a greater weight gain during pregnancy. Excessive weight gain during pregnancy is associated with differential methylation of 104 cytosine guanine dinucleotides (CpGs), which are scored for 97 gens. Among these, 4 CpGs that score for 3 genes (FRAT1, SNX5 and KCNK3), show significant associations with cardiometabolic parameters of the offspring at 6 years of age, among which the Δ BW-SDS - BMI-SDS, weight-SDS, BMI-SDS, waist-to-height ratio, visceral fat and renal fat, either at the level of DNA methylation or gene transcription.
In summary, this thesis highlights the importance of the placenta in the integration of maternal stimuli during gestation and its potential impact on the programming of the cardiometabolic risk of offspring; as well as identifying placental markers (lipid profile and DNA methylation markers) that could be used as biomarkers to predict those infants at higher risk of developing obesity and
cardiometabolic disorders.