Prof Agneta Holmäng

Programming of the Metabolic Syndrome – The Critical Role of the Maternal Metabolic Environment and Early Childhood

The prevalence of type 2 diabetes mellitus (DM) is increasing at an alarming rate and will afflict an estimated 200–300 million people worldwide by the end of the decade. Also on the rise is the metabolic syndrome, which may reflect in part a perinatal origin of adult disease. The risk of developing these diseases in adulthood is also increased by maternal obesity during pregnancy, as well as by poor nutritional conditions during fetal development. Our primary hypothesis is that maternal metabolic conditions, including obesity and intake of a Western diet, alter maternal cytokine levels, exposing the fetus to inflammatory mediators that program the fetus to metabolic syndrome in adulthood. We propose to study the mechanisms linking the unfavorable maternal metabolic environment to the development of obesity/overweight in early childhood and metabolic disease in the adult offspring.

Undernutrition at critical periods in intrauterine development is thought to increase susceptibility to disease in later life. On the other hand, over-nutrition and obesity—a rapidly growing problem in Western societies—also has large health care implications. Today, as many as 30–40% of all pregnant women are overweight or obese. If a woman becomes overweight in between two pregnancies, the risk of developing gestational diabetes during her second pregnancy is doubled compared with the risk during her first pregnancy. Overweight/obese women are also more likely give birth to babies with increased birth weight (>4 kg) referred to as large for gestational age (LGA)—a complication in >20% of pregnancies in Sweden. However, a small decrease in weight (1 BMI unit) results in a decreased risk for LGA. LGA babies have an increased risk of obesity and insulin resistance in childhood and adulthood. Interestingly, there seems to be a U-shaped relationship between birth weight and type 2 DM in later life, suggesting that both extremes of the birth weight spectrum are associated with an increased risk of disease.

The objectives of our studies are to clarify: (1) the prenatal programming consequences of maternal obesity, gestational DM, or type 2 DM with altered cytokine levels on birth weight and metabolic phenotype in humans; (2) the potential impact of nutritional factors on epigenetic dysregulation and on maternal and fetal pregnancy outcomes and possible long-term implications in humans and mice; (3) prenatal programming consequences of a diet rich in polyunsaturated n-3 fatty acids (PUFAs) in mice.