Children born to obese mothers arrive already predisposed to obesity and other health problems themselves. Exactly what happens in the uterus to transmit this risk still isn’t clear, but a new study on mice points to the placenta as a key actor. The study shows that a hormone acting on the placenta can protect the offspring of obese mice from being born overweight. It suggests ways to break the cycle of obesity in humans—although other researchers caution there's a long way to go.
Researchers discovered decades ago that conditions in the uterus can “program” a fetus to be more susceptible to certain health problems. People conceived during the 1944 famine in the Netherlands, for example, suffered higher rates of cardiovascular disease, diabetes, cancer, and other problems later in life. Recent animal studies suggest that malnourishment in the womb changes the expression of DNA in ways that can be passed down for generations. But researchers are now increasingly concerned with the opposite problem. Obese women tend to give birth to larger babies with more body fat, and these children are more likely to develop metabolic syndrome—the cluster of conditions including obesity and high blood sugar that can lead to diabetes and heart disease.
To probe the roots of fetal “overgrowth,” developmental biologists at the University of Colorado, Denver, looked to the placenta—the whoopee cushion–shaped organ wedged between the fetus and the wall of the uterus, where branching arteries from the umbilical cord take up oxygen and nutrients from the mother’s blood vessels. The placenta “has always been viewed as a passive organ—whatever happens to the mother is translated toward the fetus,” says lead author Irving Aye, now at the University of Cambridge in the United Kingdom. However, recent research has shown that the placenta is less an indiscriminate drainpipe than a subtle gatekeeper.
How the placenta passes nutrients from mother to fetus depends in part on the activity of insulin—a circulating hormone that tells fat and muscle cells to absorb glucose and other nutrients from the blood. During pregnancy, a mother’s cells become less responsive to the hormone, and that insulin resistance leaves more glucose, fat, and essential amino acids in her blood to be passed to the fetus. At the same time, insulin boosts the activity of transport proteins that move these nutrients across the placenta to the fetus. This system can pop into overdrive in obese and diabetic women who already have higher insulin levels and are prone to insulin resistance. And Aye and colleagues suspected that overactive placental transport could contribute to fetal overgrowth.
So they decided to fight hormone with hormone and to test the effects of adiponectin, a hormone made in fat cells that seems to modulate insulin activity in two different ways. First, it makes muscle cells more sensitive to insulin, lowering blood sugar. Second, it hinders insulin activity in the placenta, impeding nutrient transport. Because obese people tend to have lower adiponectin levels, the researchers wondered whether supplementing the hormone could reverse fetal overgrowth.
The researchers gave adiponectin intravenously to obese mice during the last 4 days of their roughly 3-week-long pregnancies—when the majority of fetal growth occurs. These mice normally produce offspring that are nearly 30% heavier than mice born to lean mothers. But the babies of adiponectin-treated mice were about the same weight as those born to lean control mice, the researchers report online today in the Proceedings of the National Academy of Sciences. The hormone reversed the abnormally high fetal blood sugar levels observed in the fetuses of obese mice, and it seemed to limit fetal nutrition by reducing levels of certain glucose and amino acid transport proteins at the placental barrier.
The study is “interesting from a mechanistic point of view,” says Patrick Catalano, an obstetrician at Case Western Reserve University in Cleveland, Ohio, who studies obesity during pregnancy. But he sees a major barrier to applying it to humans. Unlike human babies, mice are born without much fat, he says. Adiponectin may have reduced the weight of the newborn mice not by reducing fat deposition but by cutting their muscle mass—an undesirable outcome in human babies.
Rebecca Simmons, a neonatologist and developmental biologist at the University of Pennsylvania, agrees that the study offers important insight into fetal overgrowth, but “we’re really nowhere close to developing a drug based on this study,” she says. Because fetal overgrowth isn’t immediately life-threatening, testing a new drug might not be worth the risk of negative effects on the fetus, she says. “We have to be very, very careful.”
Still, there could be effective ways to bump up adiponectin without drugs, Aye says. Omega-3 fatty acids found in fish oil, for example, seem to modestly increase the hormone. So do behavioral changes that doctors already encourage in obese moms: diet and exercise.