Many obese women have a hard time getting pregnant. When they do, often with the help of infertility treatments, they tend to have children who are prone to obesity themselves. Now, working in mice, researchers have identified a process in egg cells that may account for both of these problems. What’s more, a new diabetes drug—now in clinical trials—may offer a solution.
This is “a new idea about how obesity affects the quality of eggs,” says David Albertini, a reproductive scientist at the University of Kansas Medical Center in Kansas City, who was not involved in the study.
Obesity doesn’t just impact a person’s lifestyle—it can also alter the way their cells work. High levels of fats and cholesterols can clog up a cell’s machinery and interfere with its ability to build fully functional proteins. More specifically, obesity stresses the endoplasmic reticulum (ER), where proteins are made and shuttled throughout the cell. This process, known as ER stress, can cause the cell to self-destruct and can occur in cells throughout the body, including the liver, pancreas, and brain.
To find out if this stress response takes place inside egg cells as well, researchers led by Rebecca Robker, a cell biologist at the University of Adelaide in Australia, turned to a mouse model of obesity that closely replicates what’s seen in humans. The aptly named Blobby mice have a genetic mutation that causes them to overeat their way to obesity on regular, low-fat mouse chow.
The researchers monitored both ER stress and the activity of mitochondria, the energy-generating machinery of cells, in the egg cells of obese and healthy mice, as well as how their egg cells faired after in vitro fertilization (IVF). When the researchers compared the patterns of gene expression in the egg cells of obese and lean mice, they found that the Blobby mice had significantly higher levels of genetic markers for ER stress. Critically, Blobby eggs also had reduced mitochondrial activity compared with their lean litter mates’ egg cells.
“When we saw that the mitochondria in the eggs were damaged, we knew that that was a very important and critical problem,” Robker says. Mitochondria in eggs are particularly important; although both parents contribute DNA to a child, mitochondria from the mother’s eggs give rise to all the mitochondria in every single cell of an offspring’s body.
The researchers found that the damaged mitochondria in the eggs of obese mice couldn’t replicate properly in the embryos. The fetuses that developed from the eggs of Blobby mice were heavier than those from skinny mice, and they had less mitochondrial DNA in their livers, kidneys, and hearts.
“This is important because it provides a new mechanism, a new understanding, for how obesity may lead to an offspring’s own propensity for obesity,” Robker says.
She and her colleagues predicted that both the cellular stress response and the mitochondrial damage could be reversed by treating obese mice with existing compounds. A stressed ER can flood a cell with calcium, and mitochondria, which help keep calcium levels in check inside cells, can then become overwhelmed and break down. Robker’s team reasoned that by tackling the problem in the ER, the benefits would trickle down to the mitochondria. Indeed, when the researchers gave the obese mice BGP-15—an ER stress inhibitor that in early clinical trials for diabetes research is already proving to be a safe and effective way to increase mitochondria in muscle cells—the eggs showed both lower levels of cellular stress and higher mitochondrial activity. And when these eggs were fertilized and transferred into surrogate mothers, they no longer grew into overweight fetuses, the team reports online today in Development.
Robker’s team is now testing whether the diabetes drug will have similar fertility-boosting effects on isolated human eggs. Still, she notes that weight loss and nutritional strategies—instead of drugs—can also keep women from having to resort to IVF. “Obese women only have to lose a small amount of weight and their natural fertility will often return.”