Saturday, April 3, 2010

Obesity & Heredity, Part 4: Epigenetics

I first heard about epigenetics from Dr. Theodore Belfor, the man behind the adult palate expansion device called the Homeoblock.  It is his opinion that epigenetics will be the most important field of science in the next decade.  In brief, epigenetics is the study of  the changes that take place within the epigenome – literally, "on top" of the genome – due to environmental factors, such as food and pollution, without affecting the DNA sequence.  Here's a more lengthy explanation from a website  published by a European group who call themselves “The Epigenome Network of Excellence:”

Conrad Waddington (1905-1975) is often credited with coining the term epigenetics in 1942 as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being”. Epigenetics appears in the literature as far back as the mid 19th century, although the conceptual origins date back to Aristotle (384-322 BC). He believed in epigenesis: the development of individual organic form from the unformed. This controversial view was the main argument against our having developed from miniscule fully-formed bodies. Even today the extent to which we are preprogrammed versus environmentally shaped awaits universal consensus. The field of epigenetics has emerged to bridge the gap between nature and nurture. In the 21st century you will most commonly find epigenetics defined as 'the study of heritable changes in genome function that occur without a change in DNA sequence.'

Take home quote from above: “...epigenetics has emerged to bridge the gap between nature and nurture.”  This is extremely important in the study of health and nutrition, as there are many questions of what brings about good health and poor health in the context of inheritance, none of which can be fully answered without evaluating specific individual choices – dietary, environmental, etc. – made within each generation (which affects future generations).   In other words, nurture – how we are taken care of as children and how we take care of ourselves as adults  – is what molds and shapes nature – the way our bodies and minds express themselves epigenetically, which is then potentially passed to our children.

How do epigenetic changes take place?  The Epigenome Network of Excellence reporter, Brona McVittie, puts it this way:

The genetic blueprint, like a complex musical score, remains lifeless without an orchestra of cells (players) and epigenotypes (instruments) to express it... Epigenetic factors include both spatial patterns, such as the arrangement of DNA around histone proteins (chromatin), and biochemical tagging...With some 30 000 genes in the human genome, the importance of silence, as with any orchestral performance, must not be underestimated...As cells develop, their fate is governed by the selective use and silencing of genes... Failure to silence genes can produce a hazardous cacophony.

What does all of this have to do with obesity?  Well, scientists have discovered that epigenetic changes in mice that are pregnant mothers can directly impact the health of the offspring.  How?  By turning on or off specific genes through dietary or environmental means.  One of these health effects, in addition to cancer and diabetes, is a tendency of the offspring to become obese as adults.  In one study, if a single gene, called the “agouti gene,” is overexpressed through the failure to suppress another gene (Avy), it greatly influences the ultimate health of the offspring (emphasis mine):

Failure to epigenetically suppress the Avy gene during development causes the agouti gene to be ectopically overexpressed later in life. This high level of agouti expression in essentially all tissues causes numerous downstream metabolic and endocrine effects that ultimately affect gross biological end points such as obesity and survival. This agouti overexpression and its physiological effects have been termed the yellow agouti obese mouse syndrome. This syndrome includes a yellow or mottled yellow coat color, altered metabolism and obesity from a young age. It also results in adult diabetes, increased cancer susceptibility and, by 24 mo of age, twice the mortality seen in normal mice.

Interestingly, whether or not a mouse becomes obese seems to depend on the levels of methyl-donating substances, such as folic acid (a vitamin naturally found in high amounts in organ meats, many kinds of legumes, and dark leafy greens).  The reason behind this has to do with the way that DNA passes information to cells in the body -- a process called  DNA methylation.  Whether or not certain genes are expressed has a lot to do with this process.  Without enough methyl-donating substances, such as the B-vitamins, betaine, choline, SAM-e and genistein (from soybeans), DNA methylation is disturbed and abnormal cell expression, along with switching on or off certain genes, results.  You can see why folic acid supplementation is recommended for pregnant women and why women in traditional cultures consume "sacred" foods rich in methyl-donating nutrients, such as liver, before and during pregnancy.

So, if obese people supplement their diet with folate or genistein, can they reverse the epigenetic changes that may have brought about their obesity?  Short answer: we don't know.  In animal studies, there's more certainty.  Here's what Randy Jirtle, an expert in epigenetics, has to say:

Weaver et al. (Nat. Neurosci. 7: 847-854, 2004) at McGill University, however, have shown recently that maternal nurturing behavior can stably alter the epigenotype in rat pups soon after birth. Moreover, these epigenetic changes are reversible in adulthood following methionine supplementation or treatment with histone deacetylase (HDAC) inhibitors (Weaver et al.Proc. Natl. Acad. Sci. USA 103: 3480-3485, 2006). Thus, data supporting the reversal of environmentally induced epigenetic changes via dietary supplementation or pharmaceutical therapy in adulthood is mounting.

The implications for humans are far-reaching.  Perhaps someday we'll have a way of epigenetically treating obesity, diabetes, and cancer.  For now, the best we can do is eat a nutrient-dense real-foods diet while avoiding processed and refined foods -- the foods that have most likely brought about our health dilemmas in the first place.

For a great overview of epigenetics, check out PBS Nova's educational page on the subject.  Also, here's a nice website by the University of Utah.

SIDEBAR: Is Plastic Making Us Fat?

Aside from diet, another significant factor in the tendency of the agouti mice to become obese comes from the mother's exposure to biosphenol-A (BPA), a common plastic found in many food and beverage containers.  Here's Randy Jirtle again to explain:

We have demonstrated recently that when female pregnant mice are exposed to BPA, the incidence of yellow Avy offspring is markedly increased because DNA methylation of the agouti gene is decreased (Dolino et al.,Proc. Natl. Acad. Sci. USA 104: 13056-13061, 2007). BPA also epigenetically alters gene expression of at least one other gene, indicating a genome-wide effect. Yellow agouti mice become obese in adulthood and have a high probability of developing diabetes and cancer. Consequently, BPA exposure leads to adult diseases in agouti mice by altering the epigenome during the earliest stages of development—a condition that can be counteracted by maternal nutrient supplementation with methyl-donating substances (folic acid, etc.) or genistein.


SIDEBAR: Weston A. Price & Epigenetics

Epigenetics may seem obvious to folks out there who are familiar with Darwin's theory of evolution.  “Of course our bodies and minds are shaped by our environment; and of course we evolve (or devolve) throughout time and generations.  That's the way nature works!”  The big difference, as far as I can tell, is that unlike DNA, epigenetic changes actually take place within one lifetime, not over eons of evolution.  The way the epigenome appears to be altered is by dramatic changes in environment, particularly diet.  Think Nutrition and Physical Degeneration or Pottenger's Cats.

Actually, one might say that Price and Pottenger recognized epigenetics when they observed physical degeneration in the people and animals they respectively studied, although they didn't call it that.  The changes in facial structure and lowered immunity in their studies appeared to be a direct result of poor diet generation after generation.  Once again, during one lifetime, the epigenome can be altered significantly.  Could it be that the mothers and fathers eating a modern diet and the cats eating cooked food altered their epigenome and then passed on these traits on to the next generation?  Is this why each generation appeared to be progressively worse than the last?  The field of epigenetics suggests this is the case.