Which has greater influence on childhood obesity, prenatal or postnatal environment?

Issue: October 2017

Click here to read the Cover Story, "Rising obesity rates impact fertility among young adults."

Periconception and in utero exposure to over- or undernutrition can result in metabolic syndrome, type 2 diabetes and obesity in offspring.

Since the mid-1990s and the introduction of the “developmental origins of health and disease” theory, evidence from both human and animal studies has confirmed that in utero exposure to extreme nutritional changes permanently programs offspring to develop adverse health conditions as adults, including cardiovascular disease, insulin resistance and type 2 diabetes. The Dutch Hunger Winter is perhaps the most dramatic example. In the winter and spring of 1944 to 1945, the Nazis occupied Holland and starved the population. It was observed that offspring of mothers exposed to famine during the intrauterine period had increased rates of obesity, diabetes and CVD as adults in the 1990s.

Subsequent epidemiologic studies reported similar findings in those who were exposed to overnutrition during pregnancy. Some of these offspring were born large for gestational age, whereas others were born small and underwent catch-up growth. The individuals at both ends of this spectrum experienced permanent physiologic and metabolic effects that predisposed them to CVD in their later years. Thus, the long-term effects of birth weight reflect a U-shaped curve in which both extremes are detrimental in later life.

Several well-studied examples in rodents have linked offspring phenotypes to epigenetic modifications thought to be induced by adverse maternal diet and other exposures. Obesity and metabolic disorders have been induced in rodent and human offspring by maternal global undernutrition, maternal overnutrition, maternal protein restriction, maternal uterine artery ligation, maternal synthetic glucocorticoid treatment, maternal anemia or prenatal cytokine exposure.

In humans, studies have connected maternal exposures during the periconception and in utero periods to metabolic disease or disease risk in the offspring. Similarly, we have only limited evidence linking maternal exposures to epigenetic changes in offspring. However, studies of the effects of the Dutch famine of 1944 provide evidence for inheritance of methylation patterns.

Women (F1) whose mothers (F0) were exposed to famine during the periconceptual period later had offspring (F2) with birth weights lower than offspring of women not exposed to famine in utero. This effect of F0 famine on F2 birth weight persisted after control for potential confounding and intervening variables. Interestingly, the F1 women who had been exposed to famine during periconception had less DNA methylation of the insulin-like growth factor II gene 60 years later than did their unexposed, same-sex siblings.

Another study linking offspring effects to methylation in humans was that of Godfrey and colleagues, who isolated DNA from umbilical cord tissue from two cohorts who were either obese or nonobese at age 9 years (Godfrey KM, et al. Diabetes. 2011;doi:10.2337/db10-0979). They looked at methylation status of the promoters of five candidate genes that had been shown to correlate with obesity in animal models. In both cohorts, methylation of retinoid X receptor-alpha in the umbilical cord was associated with adiposity at age 9, and in one cohort, methylation of endothelial nitric oxide synthase showed this correlation. These observations suggest that epigenetics is involved in fetal programming of later obesity.

Inheritance of epigenetic modifications that lead to long-term health effects is thought to have been selected for in evolution because it allows phenotypes to adapt to meet the demands of the later-life environment. For example, teleologically, the transgenerational effects of the Dutch famine could have ensured that subsequent generations were more able to store energy if the famine situation had continued. Because it did not, the next generations instead were at risk for becoming obese. Now that we are beginning to define the epigenetic mechanisms of intergenerational inheritance, we may be able to develop strategies to prevent deleterious outcomes. However, doing so will require first answering many key questions: How plastic is the system, and what are the critical windows of development at which strategies should be targeted? How many generations are required to reverse an epigenetic mark? Can surrogate markers be used to predict disease?

Kelle H. Moley, MD, is the James P. Crane professor and vice chair of obstetrics and gynecology at Washington University in St. Louis. She is chief of the division of basic research and director of the Center for Reproductive Health Sciences. Disclosure: Moley reports no relevant financial disclosures.

Our current postnatal environment encourages obesity in children.

The explosion in pediatric obesity over the past 20 years — a near doubling in prevalence to the point where almost 1 in 5 children is obese — has come at the same time as multiple environmental changes that have helped fuel this epidemic. These obesigenic changes include a spike in the amount of energy-dense, processed foods that children eat, a drop in sleep time (altering appetite-regulating hormones and enabling more time to eat) and ubiquitous screen-based entertainment that keeps children from running around outside. Children nowadays are more likely to know how to download an app on their smartphone than how to peel a banana or play leapfrog.

Each of these unhealthy habits contributes to an unbalanced equation of children taking in more calories than they expend. While genetics and intrauterine environment play important roles, their influences remain difficult to establish unequivocally. This is because mothers who struggle with obesity often have developed unhealthy habits themselves (the similar mix of unhealthy food, lack of sleep and a sedentary lifestyle), and a major reason that their children are prone to obesity is that the mothers (and fathers) have efficiently passed these bad habits on to their kids. From an obesity standpoint, these unhealthy practices have become the gift that keeps giving.

Our goal needs to be to right these wrongs. As a society, we need to turn back the clock to an earlier way of life, back when we ate more freshly prepared food with plenty of fruits and vegetables, when children got to bed on time, and when they would spend hours playing tag not Minecraft. Instead of modeling poor food choices, we should cook meals with our children and make sure our homes are free from sugary soda, juice and junk food. Instead of staying up with the kids to watch the end of the movie, we should pause it and get everyone to bed on time (or, of course, skip it entirely in lieu of reading a story). And, as parents, instead of being on our smartphones at home, we should be going on family walks and playing games with the children. Modeling these healthier choices would teach kids to tilt the energy balance back in favor of taking in fewer calories and burning more off. Healthy habits like these kept children thinner for many generations and would help us combat obesity now, too.

Mark DeBoer, MD, MSc, MCR, is a pediatric endocrinologist and associate professor of pediatrics at the University of Virginia. Disclosure: DeBoer reports no relevant financial disclosures.