Monday, March 26, 2012

Set to Be Obese? Epigenetic Programing in Utero - The Roles of Over- & Undernutrition, High & Low Protein, Fruits, Veggies, Zinc, Magnesium, Chromium, Vitamins & More

Image 1: Your mother's diet is not the sole cause of your love handles and health problems, but it could well have tipped the scale to your fat disadvantage. Don't be resentful, but don't repeat the same mistakes, either!
While it is certainly false to assume that anyone can't help but to get obese, it's similarly hard to deny that some people just have to cut back on the coke and sweets they eat to get back in shape, while others struggle with shedding superfluous weight (=fat) and regaining their health even if they are in a reasonable caloric deficit, eat a whole foods diet and exercise regularly. "It must be in my genes!" is what you will usually hear from people on both ends of the spectrum and while the former will smile at you and grab the next best snickers bar, just "to make sure that they don't lose too much weight", the unfortunate people on the other end of the spectrum are clutching to each and every straw, or, in these days of Internet quackery, "expert" advice to finally solve their life-long misery.

In today's blogpost I want to take a brief look at the leatest research into the epigenetic realities of obesity and how those nasty love-handles you have been carrying around for years, now, may actually have been "programmed" when what is now your body was still a bunch of constantly differentiating cells.

A fetus needs more than just adequate folate (let alone folic acid)

We have known for decades, that the consequences of fetal malnurishment, i.e. the insufficient provision of macro- and micronutrients, go well beyond an increase in infant morbidity and mortality. Van Assche et al. report as early as in 1977 that fetal growth retardation (due to malnurishment or other causes) was associated with reductions in both the size and the function of the pancreas (Assche. 1977); reductions, of which Hales et al. were able to show that they can lead to glucose intolerance and hypertension later in life (Hales. 1991).
Image 2: No, no, no! Juicing your fruits and downing 5-6 apples, oranges, peaches, lemons, grapefruits or whatever in one sitting is not healthy! Neither for you, nor for your offspring!
What can you do? As I said data from human studies is scarce and mostly observational, but if you are concerned about the beta-cell autoimmunity and subsequent increases in diabetes risk of your offspring, a study from the University of Tampare suggests that it may be a good idea to eat more berries (-10% risk) and to drink more coffee (-38% risk; Virtanen. 2011). If you are afraid that your offspring may be too small, you better eat fruit and veggies instead of pills, as the consumption of the former and not the total amount of micronutrients correlates with the size of a newborn (Loy. 2011). Thusly avoiding low intakes of (leafy) vegetables and (malaceous) fruits, all you need to reduce the incidence of allergic wheeze in your offspring is to make sure you get enough chocolate (low chocolate consumption = +36% increase; Erkkola. 2012) and avoid fruit and berry juices (+40% risk increase) and and you should be good to go ;-)

The overall message should yet be: Don't stuff or starve yourself and stick to the principles of healthy living I have been trying to piece together like a puzzle in the past 727 posts and the countless comments here at the SuppVersity. This will be good for you and for your offspring!
In the last decade more and more scientists have tried to elucidate the exact mechanisms behind this metabolic deteriorations. And while the increased awareness of the importance of dietary folate is probably the most prominent results of these efforts, vitamin B9 is by far not the only (micro-)nutrient in your diet which can exert far-reaching long-term effects on your offspring. And though much of the information we have is based on rodent or epidemiological human data, I believe that it is worth considering how what you eat today, may influence the health of your children in the future:
  • Micronutrient deficiency and body fat % of the offspring: In a series of studies, Rao et al. were able to show that total (-50%) micronutrient deficiency, as well as an insufficient supply of magnesium, manganese, chromium, zinc, folic acid or vitamin B12 (summary in Rao. 2012) led to statistically significant increases in body fat levels in the offspring of rats. And while the effects of maternal chromium and manganese deficiency could be corrected later in life, those that were induced by a lack magnesium, zinc and vitamin A (Ribot. 2001) in the diet of the pregnant rat dams, were permanent.
  • Exaggerated cortisol release due to high fat diet and insufficient chromium: Both a diet insufficient in the trace element chromium (Padmavathi. 2010), as well as one of the standard "high fat diets" (30% fat; 16% protein; 37% carbs; Bullo-Cioca. 2010) increased the corticosteroid (cortisol) response to stress and thusly increased the diabetes and obesity risk of the offspring of chromium deficient or HFD significantly. Unpublished results by Roa et al. suggest that a similar increase in 11-beta-HSD (the enzyme responsible for the formation of cortisol) exist for folate and vitamin B12, as well (Rao. 2012).
  • Cholesterol, triglycerides and other lipids: While an insufficient intake of manganese during pregnancy appears to make the offspring more susceptible to diabetes, obesity and low-grade inflammation, a profound lack of magnesium and zinc reduced the levels of cholesterol and cholesterol and triglycerides, respectively (Venu. 2008; Padmavathi. 2009).
  • Iron deficiency results in growth retardation and brain chemistry: Pubs born to rats on an iron-deficient diet were not only smaller and had altered lipid metabolisms, they also exhibited disturbances in brain dopamine metabolism and defects in the brain myelin (fatty layer that protects the neurons) fatty acid composition (Kwik-Uribe. 2000)
  • Reduced and exaggerated salt intake predispose to hypertension: As of late the FDA has been going back on their recommendation to avoid salt like a plague and while their reasoning was a different one, the results of a 2011 study by Kaleganova et al. confirm that both a high and a low sodium intake during pregnancy can lead to pathological changes in the kidney morpholgy of the offspring and, subsequently, to hypertension (Kaleganova. 2011)
  • Increased susceptibility to obesity in response to high-dose multi-vitamin supplementation: Although the overall message of the above effects of nutrient-depended epigenetic programming appears to be that you better make sure not to be deficient in any nutrient, the results of a 2009 study by scientists from the University of Toronto (Szeto. 2009), suggests doubling your already high-dose multivitamin "just to make sure", is probably the worst "prophylactic" measure you could resort to. After all the pubs that were born to rats who received the high dose (10x RDA) vitamin supplement in the Szeto study, were profoundly insulin resistance, hyperphagic and obese.
While some of these negative consequences of maternal and subsequent fetal mal-nutrishment are either reversible (by replenishing respective nutrients) or induced by developmental changes and consequent malfunction of organs or organ systems, it becomes increasingly clear that some of the changes are of epigenetic nature, which means that certain DNA strains are activated or deactivated via methylation in response to dietary restrictions or, as in the case of overall malnurishment or the so-called "high fat diet", an under-, respectively overabundance of energy.

Protein (mal-)nutrition during pregnancy and epigenetic consequences

Image 3: The effects of protein malnutrition on pediatric health are profound, at any age!
Of the macronutrients, dietary protein appears to exert the most profound epigenetic effects during the fetal period. The offspring of protein malnurished rats in a 2005 study from the University of Southhampton in the UK (Lillycrop. 2005), for example, had ~20% lower PPAR-alpha and glucocorticoid receptor methylation status than that of rats on a protein sufficient diet. The subsequent >10x higher PPAR-gamma and 2x higher glucocorticoid receptor mRNA expression render provide a "mechanistical" (obviously it is a physiological one, but if we think of the body as a epigenetically controlled machine, the expression "mechanistic" would be adequate) explanation for the increased susceptibility to dietary induced obesity in later life - an effect, by the way, which has only recently been shown to be sex-depended and more pronounced in female than male offspring of mice (van Straten. 2012).

A high protein content of an overall energy deficient diet, on the other hand, has recently been shown to correct the increased cardiovascular disease risk subsequent to fetal malnutrition in mouse offspring (Kavamura. 2012), which could in fact be related to a correction, or rather aversion of the detoriations in glucocorticoid receptor expression observed in the Lillycrop study (see above).
Note: A 2011 study from the Department of Nutritional Sciences at the University of Toronto suggests that even though soy may be less of a problem for women than men, you would be ill-advised to eat (or feed your pregnant wife) larger amounts of soy protein. After all, the scientists comparison of soy vs. casein based diets showed that the offspring of the soy-fed rodents exhibited increased body and fat pad weights and a statistically highly significant increase in systolic blood pressure - an effect that was, in this case, more pronounced in the male, than in the female pubs (Jahan-Milan. 2011).
Interestingly, we see very different effects with postnatal protein restrictions, only recently, a group of researchers from the Universidade do Estado do Rio de Janeiro, in Rio de Janeiro, Brazil (Lisboa. 2012), that the offspring of the dams received a low protein (8% vs. 23%) diet during the lactation period had lower adipocytes area, a higher leptin:visceral fat ratio, increased leptin receptor expression (and thusly sensitivity) and significantly higher levels of thyroid hormones (T3 and T4) at lower TSH levels than the adult offspring of mothers who had received the normal diet during lactation. These results emphasize the need for further research and confirm my repeatedly voiced concern about jumping to radical conclusions. After all, the same high protein diet that could decrease the CVD risk of your children could be one of a myriad of factors which contribute to the rampant rise of thyroid problems, these days.

Don't surrender, and outdo your well-meaning parents

If coupled with prenatal stress exposure, which has also been shown to induce profound negative effects on the glucocorticoid metabolism of the offspring (Brunton. 2010), protein malnutrition could form a "duo infernale", which would verify the initial statement that some people have an "epigenetic disadvantage" compared to others. It would yet be unfair and above all unproductive to lay the blame on your parents. After all, familial studies suggest that only 30%-50% of the weight gain could potentially be explained by (epi-)genetic factors (Lawin. 2009). This leaves a huge margin for you to intervene and still emphasizes the importance of watching your own diet - for your own, and the sake of your children and grandchildren (I guess, we forget about humanity for now ;-)