A healthy diet during pregnancy maintains the intricate epigenetic machinery that rewrites the higher order genetic structure (called the "histone code"), said a group of researchers led by Baylor College of Medicine in a recent report in the FASEB Journal.

In previous studies, Dr. Kjersti Aagaard, associate professor of obstetrics and gynecology at BCM, and her colleagues, had shown that the offspring of primate mothers who ate a high fat diet were more likely to have non-alcoholic fatty liver disease and a higher risk of obesity later in life. They did not know which components of the epigenetic machinery were responsible for these changes until they looked at the sirtuin family of proteins, already shown to tie together caloric restriction and longevity.

In this most recent study, these BCM scientists showed that SIRT1, a member of the sirtuin family, responds to excess levels of fat calories in the pregnant mom’s diet by chemically modifying key locations on the histone protein. However, the levels and activity of SIRT1 are diminished in the offspring of mothers who ate the high fat diet. Aagaard is senior author of the report.

Histones are proteins that aid in packaging DNA into chromosomes and making it possible for the DNA to be transcribed into the RNA that begins the process of making a protein. The addition or deletion of molecules to the histones so-called epigenetic changes that occur after the genetic code is written—affect how genes are expressed.

High fat diet

In the study, the scientists studied three groups of pregnant primates. One group of normal weight pregnant moms ate a healthy diet with no more than 13 percent fat while the second group ate a high fat diet of at least 35 percent fat. The second group became obese. The third group ate a high fat diet for several years and also became obese. However, just before moms in the third group became pregnant, they were given back the healthy diet.

"Because SIRT1 levels were unchanged in the mothers on the low fat diet, and only decreased with high fat diet, we are confident that a high fat diet, but not maternal obesity, is responsible for this change," said Dr. Melissa Suter, the postdoctoral associate in Aagaard’s laboratory who is first author of the report.

When researchers evaluated the SIRT1, they found that the infants whose mothers ate the high fat diet during pregnancy had less SIRT1 than those in the other groups. Infants whose mothers ate a healthy diet during pregnancy—whether the moms were obese or not—had normal levels of SIRT1 and its activity.

Cycle of obesity

She said a second result is that now they know that the sirtuins are important in translating what a mother eats to her developing infant and that they are important in writing or rewriting a developing infant’s histone code, an activity that likely has lifelong implications.

"We are finding that the cycle of obesity likely begins in the womb. However, we are also finding that obesity does not necessary beget obesity. A diet laden with fat changes the molecular machinery which chemically modifies the structure of the developing infant’s genetic material. These commonly called ‘histone code’ changes are rewritten—at least in part—by sirtuin 1, which in turn alters key regulators of fat and glucose metabolism in the infant. We believe that consuming a healthy diet in pregnancy will be of benefit to the infants of both overweight and obese women. It is our hope that these early steps will in turn break the cycle of obesity in the generations to come," said Aagaard.

Others who took part in this study include Aishe Chen and R. Alan Harris of BCM, Mahua Choudhury and Jacob E. Friedman of the University of Colorado School of Medicine in Aurora; Robert Lane of the University of Utah in Salt Lake City; Kevin L. Grove of the Oregon National Primate Research Center of the Oregon Health and Science University in Beaverton and Marie S. Burdine and Alan Tackett of the University of Arkansas for Medical Sciences in Little Rock.

Funding for this work came from the U.S. National Institutes of Health (NIH) Director New Innovator Award to Aagaard (DP2120OD001500-01); U.S. National Institute of Child Health and Human Development/National Institute of Diabetes and Digestive and Kidney Diseases and REACH IRACDA
(K12 GM084897).