Developmental programming of health and disease
Among the adult US population, cardiac and metabolic diseases have prevalences of 35% and 48%, respectively. It was traditionally believed that the risk of cardio-metabolic disease is determined by interactions among genetic and lifestyle factors. Recently, however, it has become widely established that exposure to an adverse in utero environment also increases the risk of CVD in a phenomenon called developmental programming. The intrauterine environment is now considered one of the key determinants of cardiac and metabolic health in offspring. In the US, more than 65% of women who become pregnant are overweight or obese. Obesity in pregnancy programs the offspring to experience complications in adulthood, including obesity and cardiovascular and metabolic diseases. Our team has shown that impaired immune function is crucial to this effect, with activation of chronic inflammation being required for the initiation and progression of developmental programming. Using a mouse model of maternal obesity, we found accumulation of CD4+ effector memory cells to increase in the adipose tissue of obese mothers and their offspring. Our goal is to determine whether those memory cells contribute to metabolic dysfunction in the offspring of obese mothers.
Placental adaptation to maternal obesity: Role of autophagy
The placental function is now recognized as a critical determinant of healthy fetal growth and development. Our group has shown that placental function is compromised with maternal obesity even in pregnancies with apparently “normal” outcomes. Our lab have demonstrated significant metabolic abnormalities in the placentas of obese women, including inhibition of autophagy. Autophagy is survival and a cellular recycling process, associated with sequestration and denaturation of damaged organelles, misfolded proteins and lipids. Autophagy becomes defective in aging organisms, in obesity, with metabolic syndrome or inflammation, cancer, and cardiovascular, and neurodegenerative diseases. Our lab found that mice born with a placenta-specific deletion of autophagy become obese in adult life with severe cardiac and metabolic perturbations. These data indicate that both maternal obesity and defective placental autophagy similarly alter the offspring’s phenotype. Thus, despite having such a short lifespan, the placenta plays a crucial role in the offspring’s health.