Yearly Archives: 2011 - Page 10

On Saturday’s Around the Web I linked to a study [1] that tied low-carb dieting early in pregnancy to obesity in the child at age 9. This made Ana concerned:

I’m somewhat worried about the pregnancy diet study. Actually I am trying to conceive, 3 months ago my husbund and I changed my diet to Paleo.

Now I see this study and even though I feel great, better than before, I’m not sure, how much credibility would you give it?

I presume that perhaps there could be too little fat, and with that too low calorie intake for a pregnant woman, perhaps that could be the case, opinions please!!!

We certainly don’t want Ana to be stressed out, and it’s hard to turn down three exclamation marks, so I thought I’d interrupt the cancer discussion to address her concerns.

The Study

The study [1] claimed two things:

1. Women who ate less than a thousand carb calories per day during the early part of pregnancy were more likely to give birth to babies with an overly silenced gene for the Vitamin A receptor RXR-alpha.
2. Babies born with an overly silenced gene for RXR-alpha were more likely to be overweight at age 9.

Let’s look at the second point, which is more solid, first.

RXR-alpha silencing is associated with obesity

Here is the data:

It looks like it’s normal to have about 50% RXR-alpha methylation in this promoter region and if you have 80% methylation, you’re likely to become a pudgy 9-year old.

How solid is the correlation? They replicated it in a second cohort. Their first study produced two epigenetic marks that were strongly associated with childhood obesity, RXR-alpha and eNOS. A replication study confirmed the RXR-alpha but not the eNOS association.

How plausible is it that RXR-alpha silencing would contribute to obesity? Very plausible, because RXR-alpha is the hub of a network of genes regulating most aspects of metabolism and cell activity.

Vitamin A binds to two types of nuclear receptor, RAR and RXR. When it binds to RXR, a vitamin A – RXR complex is imported into the nucleus. This then looks around for a partner. Partners of RXR-alpha include:

• Vitamin A – RAR complexes.
• Vitamin D – VDR (vitamin D receptor) complexes.
• T3 thyroid hormone – TR (thyroid hormone receptor) complexes.
• LXR (liver X receptor).
• CLOCK, the circadian rhythm regulation gene.
• PPAR-gamma (peroxisome proliferator-activated receptor), a regulator of lipids whose deficiency leads to high cholesterol and hyperglycemia.
• MyoD, a factor that triggers muscle creation.
• Many others; a list can be found at Wikipedia.

The vitamin A – RXR-alpha complex “dimerizes” with these other nuclear receptors, forming a new complex that acts as a transcription factor to turn on gene expression. Most of those other partners cannot act to turn on DNA transcription unless they dimerize with RXR.

This means that the absence of RXR-alpha would be functionally equivalent to being low in vitamin A, vitamin D, T3 thyroid hormone, CLOCK, and all those other partners. It is like being born a sun-starved hypothyroid with messed up circadian rhythms who can’t form muscle and is hyperglycemic and dyslipidemic.

All of those things are associated with obesity.

RXR-alpha silencing might be a universal component of the metabolic damage in obesity:

[A]n association between increased RXRA methylation and adiposity is consistent with the observation of strongly diminished RXRA expression in visceral white adipose tissue from obese mice (35).

Personally, I think it’s very likely that silencing of RXR-alpha promotes obesity. This is the most solid part of the paper. They have data, and the mechanism makes sense.

Conclusion: some babies are getting off to a bum start in life due to epigenetic silencing of an important gene.

Does maternal diet affect RXR-alpha silencing?

This is the really weak part of the paper. Here was their data:

When I say this was their data, this was all of it. No scatter plots, no information about how other characteristics of the diet correlate with RXRA methylation, no information about health or lifestyle characteristics of the various carbohydrate intake cohorts so that we can evaluate the possibility of confounding factors.

It is unlikely that low carbohydrate intake was causing the problem. Aside from the fact that dietary carbohydrate intake is only weakly correlated to any factors seen by the baby in the womb (eg blood glucose, insulin, etc), 261 g/day is a substantial amount of carbohydrate – well above physiological needs. So the low-carb quartile included women in glucose deficiency, glucose moderation, and glucose excess; the other quartiles only women in glucose excess. If a glucose deficiency caused RXRA hypermethylation and glucose excess caused RXRA, there would have been a much larger scatter in RXRA methylation levels among the low-carb quartile compared to the 3 higher-carb quartiles. But we can see from the graph that the standard deviations are the same in every quartile.

So there is likely to be some other factor besides carbohydrate intake that was responsible for the RXRA hypermethylation. What are the possibilities?

One possibility alluded to in the paper is that the women had low carbohydrate intake because they were starving. The paper notes that “famine during pregnancy is associated with obesity in the adult offspring (5).” However, I am unaware of recent famines in Southampton UK.

Another possibility is an excess of some other macronutrient. Those mothers who ate fewer carbs were eating more fat and possibly more protein. Given the ubiquity of vegetable oils in modern fats, the increased fat was probably largely omega-6. This raises two possibilities:

• High maternal omega-6 intake causes RXRA methylation.
• High maternal protein intake causes RXRA methylation.

Both possibilities have support from studies in rodents: maternal high protein intake and maternal omega-6 fat intake are both associated with obesity in offspring. For more on the risks of high protein, see The Danger of Protein During Pregnancy, Jul 12, 2010.

Another possibility is that the low-carb high-fat diet produced a vitamin A excess. As we discuss in the book, this is a common problem, especially among people taking a multivitamin; probably due to widespread vitamin D and vitamin K2 deficiencies, large numbers of people exhibit evidence of impaired health with vitamin A intake above 10,000 IU/day. As a fat-soluble vitamin, vitamin A intake is more or less proportional to fat intake.

If a balance between vitamin D and vitamin A is needed because the vitamin D-VDR complexes and vitamin A-RXR complexes have to be in proper proportion, then the body may respond to an excess of vitamin A and a deficit of vitamin D by upregulating VDR expression and downregulating RXR expression. Such downregulation may be achieved by RXR-alpha methylation.

Another possibility is some confounding factor that happens to be correlated with carbohydrate intake. In the US Nurses Health Study, nurses with the lowest carbohydrate intake were “rebels” who rejected not only the health advice to eat vegetable-rich and whole-grain rich diets, but also every other standard bit of health advice. The low-carb nurses smoked more, exercised less, and drank more alcohol and more coffee.

So it could be maternal smoking, lack of exercise, or drinking too much alcohol or caffeine that causes RXRA hypermethylation and childhood obesity.

Another possibility, raised in the comments by Amber, is that mothers of the obese children were obese themselves, ate low-carb diets for weight control reasons, and passed on their obesity to their children. It is indeed the case that obese mothers tend to have children who are obesity-prone, and it is suspected that epigenetics may be responsible for this “inherited” obesity. If low-carb diets have indeed become popular among the obese mothers of Southampton UK, then this is a possibility that must be considered.

Low-Carb Paleo Pitfalls?

Should Ana modify her diet because of this study?

I think it’s important to avoid a glucose deficiency. But I don’t think it’s necessary to eat 1,000 calories per day of carbs to achieve that.

I think it’s important to eat a moderate amount of protein, neither too much nor too little; and to limit the amount of omega-6 fats eaten.

I think it’s a good idea to avoid alcohol or excessive consumption of bioactive beverages like coffee during pregnancy. Also to avoid smoking, and to get some exercise and sun exposure.

If you’re doing all these things, I don’t think you need to be concerned. Ana says, “I feel great, better than before”; that’s good evidence that she’s well prepared for a healthy pregnancy.

Conclusion

The paper presents solid evidence that hypermethylation of RXR-alpha in the womb predisposes children to become obese at age 9.

The paper gives us essentially no evidence at all as to what causes hypermethylation of RXR-alpha in the womb, except that it correlates with low carbohydrate consumption in the women of Southampton UK.

I hate it when journals do this. If you’re going to link carb intake to RXRA methylation, give some real data and analysis. Probably the authors are saving their dietary analysis for a future paper. The carb graph was included as a “teaser” to make the work seem more interesting.

There are many known health dangers which are known risk factors for obesity and which correlate with low carbohydrate consumption in the general population. So until more evidence emerges, I think there’s little here for low-carb Paleo dieters to be concerned about.

References

[1] Godfrey KM et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011 May;60(5):1528-34. http://pmid.us/21471513.