Obesity is a risk factor for non-communicable diseases (e.g. cardiovascular diseases, diabetes, cancer) and its consequences are even worse in pregnant women. Indeed, obesity during pregnancy not only predisposes the mother to a multitude of obstetrical complications, but can also contribute to create a suboptimal intrauterine environment for the fetus, increasing individual vulnerability to disease. Many studies indicate an association between maternal obesity and neurodevelopmental disorders, including autism spectrum disorders, mood disorders and cognitive deficits. However, the mechanisms underlying these long-term negative effects still need to be elucidated. During ontogeny, many biological systems cooperate in order to ensure the proper development of the brain: the occurrence of maternal obesity during sensitive developmental periods could perturb the metabolic homeostasis with harmful consequences for fetal brain. The insulin/insulin-like growth factor (IGF) signaling pathway plays a crucial role in neurodevelopmental processes including neurogenesis, synaptogenesis and neuronal differentiation. Alterations in the functionality of this axis may be responsible for the negative effects of maternal obesity on fetal brain development. Moreover, the insulin/IGF system is expressed in the placenta, modulating the amount of glucose and insulin reaching the fetus, and this is possibly interconnected with the functionality of the insulin/IGF system in fetal brain. This study hypothesizes that maternal obesity might alter the expression of placental genes involved in the insulin/IGF system, negatively affecting the fetal brain. I will assess the gene expression of IGF1, IGF2, IGF binding proteins, insulin receptors and IGF receptors in placenta and fetal brain to verify the role of this system in an animal model of maternal obesity. This study will deliver biomarkers from the placenta as a tool to evaluate risks for neurodevelopmental disorders early following birth.
Maternal obesity constitutes an escalating individual, societal and medical challenge in the 21st century. The World Health Organization estimates worldwide about 3 billion of people are obese or overweight with continuous rising trends accompanied by increased consumption of junk food and reduced physical activity. A growing body of literature links maternal obesity to a higher risk to develop neurodevelopmental and neuropsychiatric disorders in the offspring. However, a mechanistic understanding of how prenatal exposure to obesity could lead to an increased vulnerability to neurodevelopmental morbidity has not been identified yet. The purpose of this research is to investigate, through a targeted transcriptomic approach, the placental derangement in the insulin-IGF signal as mediator of maternal obesity on offspring neurodevelopment, also predicting deficits in the functionality of the same system in fetal brain. In this context, the use of animal models plays a crucial role allowing the manipulation of an extremely critical stage of life as the intrauterine development. This grant would allow me to obtain key data regarding metabolic mediators underlying the long-lasting effects of maternal obesity on fetal brain development, contributing to expand the general knowledge about this topic. The high innovative aspect of this approach consists of linking and comparing both peripheral (placenta) and central (fetal brain) tissues, in order to improve diagnostic tools able to identify early risks of neurodevelopmental disorders. Indeed, the placenta, which is a much-neglected temporary organ, could become a very valuable tool for early prevention, since pregnancy may represent a crucial window of opportunity for interventions.