Fetal programming and metabolic syndrome

Abstract

Metabolic syndrome is reaching epidemic proportions, particularly in developing countries. In this review, we explore the concept-based on the developmental-origin-of-health-and-disease hypothesis-that reprogramming during critical times of fetal life can lead to metabolic syndrome in adulthood. Specifically, we summarize the epidemiological evidence linking prenatal stress, manifested by low birth weight, to metabolic syndrome and its individual components. We also review animal studies that suggest potential mechanisms for the long-term effects of fetal reprogramming, including the cellular response to stress and both organ- and hormone-specific alterations induced by stress. Although metabolic syndrome in adulthood is undoubtedly caused by multiple factors, including modifiable behavior, fetal life may provide a critical window in which individuals are predisposed to metabolic syndrome later in life.

Figure 1

Critical windows of sensitivity during human pregnancy for the development of components of metabolic syndrome later in life. The different effects of stress during pregnancy can be explained by the cellular events that occur during particular periods of pregnancy. Data were obtained from the Dutch Famine Cohort (26). Glucose intolerance is a common consequence of in utero stress and is independent of the time of occurrence. Stress in early gestation leads to a greater risk of an abnormal atherogenic lipid profile, obesity in women, and coronary artery disease. Stress in the second trimester of pregnancy, during which the number of nephrons increases rapidly, is associated with a 3.2-fold increase in risk for microalbuminuria. Finally, stress during the third trimester of pregnancy, when fat deposition occurs, has a relatively higher effect in reducing birth weight. Additional windows of sensitivity include the preconception and the early postnatal periods. Surprisingly, animal studies show that even stress limited to the preimplantation period (5 days) can lead to impaired glucose intolerance (96, 97).

Figure 2

(a) Mechanisms of in utero stress. Very different types of in utero stress can affect a fetus’s health outcome. The most common experimental procedures used in animal models to study reprogramming are highlighted in yellow. The less-studied or more-difficult-to-study factors for reprogramming are in gray. (b) As a consequence of in utero stress, the organism reprograms its development at the cellular, tissue, and systemic levels. Overall, an organism stressed in utero will manifest a metabolism that favors lipid storage and increased cardiovascular reactivity, both of which are key components of metabolic syndrome. HPA axis denotes hypothalamic-pituitary-adrenal axis.