Obese pregnant women often give birth to babies at higher risk of obesity and metabolic disease.
As rates of obesity among pregnant women continue to rise, researchers at the University of Colorado Anschutz Medical Campus have identified a promising intervention that, in animal studies, reduced or eliminated the risk that offspring of obese mothers would be born oversized or predisposed to obesity. The team focused on the hormone adiponectin, which plays a critical role in regulating insulin sensitivity and nutrient transfer across the placenta.
“In the U.S., nearly two-thirds of women enter pregnancy either overweight or obese,” said study senior author Thomas Jansson, MD, PhD, of the CU School of Medicine. “Maternal obesity increases the risk of gestational diabetes, preeclampsia and preterm birth, and it is often associated with babies who are larger and carry more fat at birth.”
These infants frequently remain at higher risk for obesity and metabolic problems later in life, perpetuating a cycle that contributes to the broader obesity epidemic. To test interventions that might break that cycle, the researchers examined adiponectin, a hormone produced by fat tissue that enhances insulin sensitivity. High adiponectin levels are protective against obesity and diabetes, while low levels are linked to metabolic disease.
Adiponectin also appears to act as a regulatory “brake” on nutrient transfer from mother to fetus through the placenta. When maternal adiponectin levels are low, that brake is released and the placenta transfers more nutrients, which can result in fetal overgrowth and increased fetal fat deposition.
In the current study, the investigators infused adiponectin into obese pregnant mice during the final four days of the 20-day gestation period, restoring adiponectin to normal levels. The treatment produced striking effects on placental function and fetal outcomes.
“Adiponectin infusion completely reversed the adverse changes we observed in the placenta of obese dams,” Jansson reported. “Pups born to obese mice that received adiponectin had normal birth weights and normal blood glucose levels. In other words, we were able to prevent the typical negative consequences associated with maternal obesity in this mouse model.”
According to the authors, this is the first experimental demonstration that normalizing maternal adiponectin in an animal model of obesity can restore healthy placental signaling and nutrient transport, and thereby prevent fetal overgrowth. The treated animals showed normalized maternal insulin sensitivity and corrected placental signaling pathways that control nutrient transfer.
The findings have translational potential. Jansson noted that pharmacologic approaches that mimic or raise adiponectin levels are under development. “A compound that produces adiponectin-like effects and can be administered safely could, in principle, reproduce these benefits in humans,” he said. Other research groups have created orally available compounds that act similarly to adiponectin and are advancing into clinical trials, although more work is needed before any clinical recommendations can be made.
The research team emphasized the need for additional studies to evaluate long-term outcomes following maternal adiponectin treatment, including whether early normalization of fetal growth leads to sustained reductions in obesity and metabolic disease risk across the lifespan.
“These results lay groundwork for interventions aimed at breaking the intergenerational cycle of obesity,” Jansson said. “If maternal adiponectin can be safely and effectively modulated in pregnant people, it may provide a targeted way to protect fetal development and reduce future metabolic disease risk.”
The study was published in the Proceedings of the National Academy of Sciences. Co-authors include Fredrick J. Rosario, PhD; Theresa L. Powell, PhD; and Irving L. M. H. Aye. The research used a mouse model that shares several metabolic features with obese pregnant women and demonstrates how maternal adiponectin functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function.
Source: UC Anschutz newsroom (University of Colorado Anschutz Medical Campus)
Abstract
Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth
Mothers with obesity or gestational diabetes mellitus typically have reduced circulating adiponectin and often deliver infants who are large for gestational age with increased fat mass. These newborns face higher risks of perinatal complications and later development of metabolic syndrome. To examine whether the inverse correlation between maternal adiponectin and fetal growth reflects causation, the researchers supplemented adiponectin in obese pregnant mice. Obese dams showed increased circulating leptin, insulin, and C-peptide and reduced high-molecular-weight adiponectin late in gestation. Their placentas exhibited activated insulin and mTORC1 signaling, reduced PPARα phosphorylation, increased in vivo transport of glucose and amino acids, and resulted in fetal weights that were substantially higher than controls. Maternal adiponectin infusion during late pregnancy normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARα signaling, nutrient transport, and fetal growth without reducing maternal fat mass. These results support the concept that adiponectin links maternal adipose tissue to placental function and fetal growth, and suggest that improving maternal adiponectin levels may be an effective strategy to prevent fetal overgrowth driven by maternal obesity.