Long-term effects of prenatal exposure to high-fat diet in an animal model of reduced oxidative stress

Obesity is a world-wide health problem. The increasing incidence of this pathology among women of reproductive age and children highlights the main question of the role played by maternal obesity in setting up a state of individual susceptibility to metabolic disorders in the adult offspring. A growing body of evidence suggests that maternal obesity and maternal adiposity, per se, are associated with adverse acute maternal and neonatal outcomes. It has been stated that maternal obesity and, more in general, maternal over-nutrition, such as maternal feeding a diet rich in fats (high-fat diet - HFD), are strongly associated with a raised offspring susceptibility to cardiovascular disease (CVD) and metabolic impairment, such as hyperglycaemia and hyperinsulinemia, type 2 diabetes (T2D) and obesity at adulthood. Obesity is a pathophysiological condition characterized by a low-grade chronic inflammation which contributes to the mechanism for obesity-related metabolic syndrome, insulin resistance (IR) and diabetes. Increased physiological levels of oxidative stress (OS) may be causatively linked to the development and progression of complications associated to obesity and over-nutritional state. Clinical as well as experimental studies support the theory of the “developmental origins of health and disease” according to which the prenatal environmental adversities may exert lifelong consequences by programming the offspring’s development. However, a comprehensive and multi-levels characterization of the long-term impact of maternal HFD is still lacking. In addition, very few studies have paid attention to the long-term effects of exposure to a maternal HFD during the in utero life only. The general aim of the work presented in this thesis was to evaluate the impact of maternal HFD both on mother and offspring in a long-term perspective and to study the effects of metabolic disturbances occurring in a sensitive time window of the individual life (i.e. fetal development and pregnancy) on the stress response, as well as on the metabolic and emotional profiles. We also aimed at investigating the interaction between an early metabolic stimulus (maternal HFD) and a physiological condition of reduced OS. In particular, in Chapter 2, we report about the long-term effects of prenatal exposure to maternal HFD assessing the metabolic, neuroendocrine as well as the behavioral profile of young adult offspring in a transgenic mouse model characterized by reduced oxidative stress, the p66Shc-/-. In Chapter 3 we report the effects of a prenatal exposure to N-acetyl-cysteine, a drug characterized by remarkable antioxidant properties, to thwart the physiological response to maternal HFD in utero. These studies relied on the assessment of a physiological (Chapter 2) or pharmacological (Chapter 3) condition of reduced OS able to represent a protective condition toward the maternal HFD. Chapter 4 describes the effects of HFD feeding before and during pregnancy on the neuroendocrine and behavioral profile of dams in the perinatal period. In addition, in this chapter we propose to investigate the potential role of HFD as a metabolic stressor for the mother with a negative impact for the developing fetus. Results are discussed considering the impact of HFD feeding during pregnancy on the dam and the possible consequences on the offspring at multiple levels (behavioral, metabolic and endocrine). Particular attention has been paid to a physiological or pharmacological condition of reduced OS as a potential protective factor. Results obtained in this thesis might drive the attention on selected markers useful to detect potential unhealthy states and to develop future preventive strategies as well as pharmacological therapies to limit the effects associated to maternal HFD.