Researchers at UAB, part of a four-center study analyzing obesity as part of the American Heart Association’s Strategically Focused Research Network, are studying mechanisms and therapeutic targets in obesity.

A summary of this network’s research was published in the Journal of the American Heart Association in February 2023, and includes work from the UAB group suggesting that what happens in the womb could determine whether the offspring will develop obesity or other metabolic diseases later in life.

The center at UAB consists of three groups analyzing the mechanisms of the transgenerational impact of the mother’s obesity and the effects on offspring.

The first group, led by W. Timothy Garvey, M.D., center director, professor with the UAB Department of Nutrition Sciences in the UAB School of Health Professions, and associate director of the UAB Comprehensive Diabetes Center, and Kirk Habegger, Ph.D., associate professor in the UAB Division of Endocrinology, Diabetes and Metabolism, and fellow Rogerio Sertie, Ph.D., looked at how a mother’s diet during pregnancy—whether she ate too much or too little—affected her offspring’s body composition and metabolism.

When mothers were fed a high-fat diet during pregnancy, their offspring had a greater risk of obesity and consumed more food, despite having high levels of hormones that regulate hunger and metabolism.

The study also looked at how the in-utero environment affects the expression of certain genes involved in metabolism and fat distribution, by examining a chemical process called DNA methylation in the brains of the offspring. The researchers found that differences in DNA methylation at specific gene sites are associated with obesity and metabolic diseases in the offspring. These findings provide important insights into how early-life events can impact health later in life and could lead to new ways to prevent and treat these conditions.

Maternal obesity and gestational diabetes mellitus give rise to epigenetic modifications at gene loci affecting insulin and leptin signaling, inflammation, and percent body fat.

The second study group, led by Ashley Battarbee, M.D., assistant professor in the UAB Division of Maternal-Fetal Medicine (MFM), and Lorie Harper, M.D., former UAB MFM faculty, aims to understand how the in-utero environment affects the health of newborns and infants up to 3 months old.

The study enrolled pregnant women who were at or after 36 weeks of pregnancy, separated them into groups based on their weight status and whether they had gestational diabetes, and tested to see whether the differences in the in-utero environment led to differences in the health of their babies. The researchers hypothesized that exposure to maternal obesity, with and without gestational diabetes, during pregnancy has an impact on the metabolic phenotype of infants at 3 months old, leading to increased fat accumulation. They also hypothesized that the same epigenetic modifications associated with cardiometabolic disease traits in older children would also be present at the time of birth. Analyses for this project are ongoing.

The third study group, led by Paula Chandler-Laney, Ph.D., associate professor in the Department of Nutrition Sciences, Bertha Hidalgo, Ph.D., associate professor in the UAB School of Public Health, and fellow Samantha Martin, Ph.D., enrolled mother-child pairs to investigate the effects of maternal obesity with and without gestational diabetes on obesity and cardiometabolic traits in both mothers and children.

The researchers found that mothers with a history of obesity during pregnancy had a poorer cardiometabolic phenotype compared to mothers who had a normal body mass index during pregnancy. However, the severity of this phenotype varied depending on whether the mother also had gestational diabetes. Children’s cardiometabolic traits were modestly correlated with those of their mothers, but only adiposity significantly differed across groups.

The study also looked at the epigenetic signatures of mothers and children ages 4-10. Epigenome-wide association studies found several genes associated with cardiometabolic disease phenotypes, including those involved in leptin and insulin signaling, inflammatory responses, and cellular vesicular trafficking.

The researchers suggest that cardiometabolic health following in-utero exposure to maternal obesity or gestational diabetes may become more pronounced once children reach puberty or adolescence.

Ultimately, the researchers hope to identify modifiable risk factors that can prevent lifelong obesity and cardiometabolic disease in infants with in-utero exposure to maternal obesity and/or gestational diabetes. Together, work from these projects sheds light on the importance of a healthy in-utero environment for the lifelong health of babies and highlights the need for interventions to prevent obesity and related conditions.

-By Adam Pope