Children's Hospital Los Angeles Researchers Link Maternal Diabetes to Obesity in Offspring

A Team Led by Sebastien Bouret, PhD, Finds That Diabetes During Pregnancy Disturbs Normal Development of Appetite-Related Brain Circuits

LOS ANGELES--(BUSINESS WIRE)-- A research team at The Saban Research Institute of Children's Hospital Los Angeles has made critical discoveries demonstrating that maternal diabetes during pregnancy triggers obesity in the offspring and sets them up for lifelong health issues.

Photo courtesy of Sebastien Bouret, PhD

Photo courtesy of Sebastien Bouret, PhD

The investigations led by Sebastien G. Bouret, PhD, provide new insights into the biological mechanisms by which the prenatal environment contributes to obesity and diabetes—findings that may lead to new therapeutic options for children and adults.

The study, “Maternal Diabetes Compromises the Organization of Hypothalamic Feeding Circuits and Impairs Leptin Sensitivity in Offspring,” will appear in the November 2011 journal Endocrinology. Lead author is Sophie Steculorum, MSc.

The team’s findings come at a critical time. According to the Centers for Disease Control and Prevention, childhood obesity has more than tripled in the past 30 years. Recent statistics estimate that 22 million children under the age of 5 are overweight worldwide. One of obesity’s primary consequences—type 2 diabetes—has been reported with increasing frequency among U.S. children and adolescents.

In earlier investigations, Dr. Bouret’s team found that the fat hormone leptin can fundamentally alter the brain’s circuitry in areas that control appetite. Now the researchers have determined that the development of the hypothalamus, a part of the brain that plays a role in eating and body weight regulation, is greatly influenced by maternal insulin, a hormone that normally control blood sugar levels.

“The gestational and early postnatal periods represent important periods of vulnerability, during which alterations in the intrauterine environment may have long-term and potentially irreversible consequences on neuron growth and connectivity,” said Dr. Bouret, a member of The Saban Research Institute’s Developmental Neuroscience Program and an assistant professor of Pediatrics at the Keck School of Medicine of the University of Southern California (USC).

Investigators also found that offspring born to diabetic mothers experienced impaired metabolic regulation during adulthood, marked by increased fasting glucose and insulin levels. The offspring had higher body weights at birth and these elevated body weights persisted into adulthood. Moreover, the ability of leptin to induce weight loss was curtailed in mice born to diabetic mothers.

Underlying all of these problems were miswired neural circuitry—specifically, abnormally organized feeding pathways—precipitated by maternal diabetes. Together, these findings provide evidence that a balanced perinatal hormonal environment is an important determinant of future weight gain and obesity—in other words, children are likely to be what their mothers eat during pregnancy.

“People have long suspected that brain circuits involved in appetite in a developing child can be disrupted when mom has diabetes during pregnancy,” noted Thomas A. Buchanan, MD, chief of the Division of Endocrinology and Diabetes in the USC Keck School of Medicine. “This paper shows very elegantly that the suspicion is true and identifies some of the important pathways that may lead to obesity and, eventually, diabetes in offspring.”

The next step, added Dr. Buchanan, will be to determine whether effective treatment of diabetes can prevent such consequences and reduce the risk of diabetes transmission from mother to child.

Dr. Bouret envisions interventional studies to alleviate and “hopefully reverse the metabolic malprogramming of fetuses and neonates born to diabetic mothers.” First, researchers must better understand the vulnerable development period when the hypothalamus responds to hormonal changes. To date, all studies have been conducted in rodents. “There is also an urgent need for an in-depth characterization of hypothalamic development in humans,” he said.

In 2010, Dr. Bouret received a $1.68 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases to support his inquiries into leptin’s role in the development of neurological structures that regulate metabolism and weight throughout life. The current studies also received support from the USC Center for Transdisciplinary Research on Energetics & Cancer.

About Children’s Hospital Los Angeles

Children's Hospital Los Angeles has been named the best children’s hospital in California and among the best in the nation for clinical excellence with its selection to the prestigious US News & World Report Honor Roll. Children’s Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States and is one of America's premier teaching hospitals, affiliated with the Keck School of Medicine of the University of Southern California since 1932.

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Photo courtesy of Sebastien Bouret, PhD