High fat diet in pregnancy changes metabolome of mother, offspring

HOUSTON -- (September 4, 2009) -- A high fat diet during pregnancy not only results in offspring with fatty livers, but actually changes the small molecules that govern metabolism, said a consortium of researchers led by those from Baylor College of Medicine in a report that appears in the current issue of the American Journal of Obstetrics and Gynecology.

"We had previously shown that the offspring of animals fed a high fat diet develop the fatty liver disease frequently found in obese humans," said Dr. Kjersti Aagaard-Tillery, assistant professor of obstetrics and gynecology at BCM. "We have been able to link these findings to significant epigenetic changes in the chromatin structure in the liver of these same offspring." (See http://www.bcm.edu/fromthelab/vol07/is7/0908-1.html and http://jme.endocrinology-journals.org/cgi/reprint/JME-08-0025v1.)

Fatty acids, amino acids affect fat storage

In this study, she and her colleagues from the University of Utah Health Sciences in Salt Lake and the Oregon National Primate Research Center in Beaverton analyzed blood from the mothers and offspring using gas chromatography-mass spectrometry-based metabolomics. They identified changes in the small molecules such as fatty acids and amino acids that are most likely to affect energy use and fat storage. They compared three different groups:

Mothers fed a control diet of which 13 percent was fat and their offspring
Mothers who ate a high fat diet (35 percent of calories) and their offspring
Mothers who were obese but who were on a control diet during pregnancy and their offspring

"Those different combinations allowed us to tease out which metabolites mirror obesity and which mirror a high-fat diet," she said. "Understanding this will help us direct our research to those pathways that, at the end of the line, we know are different by virtue of the mom's obesity versus her fat intake."

Identifying subtle differences

The measuring techniques allowed her and her collaborators to identify very subtle differences in the metabolic footprint encompassing over 1,300 chromatographic features. For example, they found that while one isomer or form of a chemical called 3-hydroxybutyrate was significantly upregulated or increased in offspring of animals that received a high fat diet, its close isomeric cousin 2-hydroxybutyrate was downregulated. Such subtle differences in the metabolic footprint are important to resolve.

The chemical 3-hydroxybutyrate indicates disrupted energy metabolism and serves as a substrate or basis for fat synthesis in the liver. In the mothers on the high fat diet, its level in the fetus was 2.3 times greater than that of the mothers on the control or normal diet.

However, when the obese mothers were put on a control diet, their offspring's 3-hyroxybutyrate levels were still higher than those of the control group, while their liver triglyceride levels were only slightly higher.

"The difference is that the mother is obese," said Aagaard-Tillery. "This suggests that the there is an effect of the mother being obese exclusive of the high fat diet in some metabolites, such as 3-hydroxybutyrate, which does not always parlay into higher triglycerides nor non alcoholic fatty liver disease".

Impact on the future?

Some of the findings were unexpected, and Aagaard-Tillery hopes to find out what they mean in determining the physiology behind their observations on an increased risk for developing obesity later in life. For example, they expected to find high cholesterol in the mothers on the high fat diet, and they did, but their offspring had lower cholesterol levels at the time of delivery. This occurs probably because the fat is sequestered in the fatty livers and placentas of these offspring. Similarly, they found that while alpha tocopherol (a chemical related to vitamin E) was high in the mothers, it was lower in their offspring.

"That fits with our cholesterol findings," said Aagaard-Tillery. "Since antioxidant and inflammatory pathways are upregulated in conditions of obesity."

Others who took part in this work include Dr. James Cox and Dr. Robert H. Lane of the University of Utah, and Sarah Williams and Dr. Kevin Grove of the Oregon National Primate Research Center and the Oregon Health & Science University. Dr. Aagaard serves as the senior and corresponding author on this study.

Funding for this work came from the National Institutes of Health, of which Aagaard-Tillery is a New Innovator Award recipient.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab.