In honor of the U.S. national day of gustatory indulgence, I thought I’d write about girth and fat. EpiExperts Twitter friend Graham Burdge and colleagues at the University of Southampton in the United Kingdom just published an interesting paper exploring how the fat content of a mother rat’s diet affects the polyunsaturated fats in her offspring’s cells and plasma, as well as how that diet may accomplish that feat — apparently it involves promoter methylation of the gene Fads 2.
But first, girth. My co-blogger Nicole recently tweeted a blog post from U.S. National Institutes of Health Director Francis Collins, who shared a map by the U.S. Centers for Disease Control showing how obesity has swept the country since 1985. It’s bracing, to say the least.
Here’s an animated version by BuzzFeed. [Ed. -- For some reason I'm having trouble embedding the video. The text link leads to that video, while the picture link below leads to Collins's blog post again.]
(For reference, adults with a BMI of 30 – 39.9 kg/m² are defined as obese. Calculate your BMI by multiplying your weight [in pounds] by 703, dividing that number by your height in inches, then dividing that answer again by your height in inches.)
The usual suspects in this ongoing demographic train wreck are sedentary lifestyles, stress, and poor eating habits. And in that last category, the adoption of Western-style diets high in saturated fats and sugars is often associated with the obesity scourge’s spread to other countries.
On to the paper by Samuel Hoile, Graham Burdge, et. al, which is an attempt to see just what happens in animals who do a bit of that fat-eating.
What’s interesting is that it sheds light on what happens when a mother rat’s diet influences the mixture of fatty acids that her offspring’s cells make and store in their cell membranes (and release into plasma) in the form of phosphatidylcholine and its molecular relatives. To be clear, it’s mostly already established that a mama rat’s high-fat diet changes offspring fatty acid metabolism — lower levels of arachidonic acid (ARA) and docosahexaenoic acid (DHA), in this line of research – the new paper links that phenomenon to epigenetic influence through the gene Fad2. In fact, it appears that although a pregnant mama rat’s high-fat diet can cause persistent changes in how much ARA and DHA her offspring make, a non-pregnant adult rat can experience the same diet-related metabolic changes, but they’re only temporary.
And of course, if epigenetic influence is responsible for these specific ARA- and DHA-related metabolic differences, then epigenetics is a decent candidate for explaining how a mother rat’s diet causes other changes in offspring metabolisms, such as vascular problems, difficulties with glucose metabolism, and so forth.
Now, it’s tempting to use these rat results to draw conclusions about the ramifications of fat in human diets, but there’s too much metabolic difference between the species for that. Also, while the Burdge group’s results achieved statistical significance, this study used six rats per diet cohort, and a larger sample size would of course provide a bit more certainty about the conclusions.
So what’s the health effect on these rat offspring who have lower levels of ARA and DHA in the cell walls of their aortas and livers, as well as in their plasma? Even in rats, the ramifications aren’t clear. Levels of ARA and DHA affect physical membrane qualities — possibly changing vascular pliability, for example. And they contribute to the pool of precursor fatty acids from which cells make lipid second-messengers, so any change might affect how much of each product gets made.
Additionally, there’s also the role of DHA in forming the nervous system tissue of a developing fetus. In rats (and humans), females keep elevated levels of DHA in their livers and plasma, compared to males — and even higher levels during pregnancy. As Burdge and colleagues — and others — suggest, a higher day-to-day level might help females more easily ramp up DHA to the pregnancy level. As a result, it’s possible that when a mother rat eat a high-fat diet during pregnancy, she’s not only impairing her daughter’s ability to synthesize certain fatty acids, she’s hindering her daughter’s ability to provide the right fatty acids to the grandchild generation in utero.
Or is it “grandpups?”
In any case, Burdge and colleagues fed each of their six-rat groups with either butter or fish oil in different amounts: 3.5%, 7%, or 21%. These six diet-cohorts continued on their regimens from two weeks before conception until weaning, while the offspring all ate a diet of 4% soybean oil.
Surprisingly, at least for me, when it came to reducing the ARA and DHA in her offspring, it didn’t make a big difference whether a mama rat ate a high-fat butter diet or a high-fat fish oil diet. After all, fish oil is high in DHA. But on either regimen, a high-fat diet meant lower levels of these two polyunsaturated fats in the livers and plasma of her adult pups.
[Update Nov. 21, 2012: In an email conversation, Dr. Burdge points out that they'd purposefully fed only ARA and DHA precursors to adult offspring in order to test their ability to synthesize these fats themselves. There's no reason to think that a mother rat's high-DHA diet is going to encourage her offspring to keep DHA levels high, and I see that's what I implied in the paragraph above. Still, it's surprising that both butter and fish oil lead to offspring with same low DHA and ARA fatty-acid synthesis regimes.]
Measuring mRNA expression of the gene Fads2 — which encodes the enzyme Δ6 desaturase (the rate-limiting enzyme in rats’ polyunsaturated fat synthesis) — the Burdge group found it to be low in rats born from mothers who ate high-fat diets, but higher in rats who ate less fat during pregnancy. That lower gene expression wasn’t dramatic enough to account for all the ARA and DHA reduction, though.
At the epigenetic level, the University of Southampton researchers found that in the liver promoter of Fad2 in adult offspring, methylation of three CpG sites was associated with lower Fad2 mRNA expression. And methylation at one of those CpGs coincided with low ARA and DHA in liver and plasma, accounting for the majority of this fatty-acid variation in both male and female rats.
The Burdge group feels this might show that Fad2 epigenetic regulation plays an important role in controlling ARA and DHA levels. And in fact, when the team tested the effect of fatty diets on non-pregnant rats, they found the same effects on Fad2 mRNA, promoter methylation, and liver ARA levels.
But perhaps most interesting is that in non-pregnant fat-fed rats — versus the offspring of fat-fed rats — these effects wore off. In the offspring of fat-fed rats, the low levels of polyunsaturated fats, low Fad2 mRNA, and higher Fad2 promoter methylation appeared to be long-lasting. As Burdge, et. al put it:
These findings suggest that there is epigenetic plasticity in the Fads2 gene in adulthood and that fat intake can alter the DNA methylation of its promoter. However, unlike exposure to an HF diet during development that induced a persistent change on Fads2 methylation and expression, there appears in adulthood to be a homeostatic mechanism that returns the level of methylation and transcription of the original state after the period of HF feeding ended.
And there’s the happy ending, as well as my opening for a tangential reference to this Thursday’s eating festival: At least in non-pregant rats, it’s possible to really overdo it for quite awhile and still avoid at least one long-term negative consequence.
[The fat turkey picture at the top is by Flickr user Dendroica cerulea, and it's reproduced here under a Creative Commons license.]
Hoile, S., Irvine, N., Kelsall, C., Sibbons, C., Feunteun, A., Collister, A., Torrens, C., Calder, P., Hanson, M., Lillycrop, K., & Burdge, G. (2012). Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver The Journal of Nutritional Biochemistry DOI: 10.1016/j.jnutbio.2012.09.005