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Obesity, Epigenetics, and Gene Regulation

By: Jill U. Adams, Ph.D. (Freelance Science Writer) © 2008 Nature Education 
Citation: Adams, J. (2008) Obesity, epigenetics, and gene regulation. Nature Education 1(1):128
Of two genetically identical mice, how can one be small and another fat? Research on epigenetic changes resulting from the environment can give us clues into obesity in mice--and humans.
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A photograph shows three agouti mice with different phenotypes standing against a red background. The mouse at left is yellow and obese. The middle mouse is yellow with dark brown fur along its back and is slightly overweight. The mouse at right is dark brown and normal weight.
FIgure 1: Genetically identical, epigenetically different
These three mice are genetically identical. Epigenetic differences, however, result in vastly different phenotypes.
© 1994 Nature Publishing Group Duhl, D. et al. Neomorphic agouti mutations in obese yellow mice. Nature Genetics 8, 60. All rights reserved. View Terms of Use

Our genome contains all the information to make us who we are, but many of the details of our behavior and appearance are actually determined by gene regulation. A striking example of the power of gene regulation is seen in agouti mice, in which genetically identical twins can look entirely different in both color and size. For example, one mouse may be small and brown, but her twin sister may be obese and yellow. Another genetically identical sister may have a mottled look with both fur colors present and fall in the middle of the weight range. The genome of each of these mice is the same, but the gene expression obviously differs (Figure 1; Duhl et al., 1994).

In these mice, the epigenome is what makes the difference. Picture a network of molecules that are intimately intertwined with nuclear DNA and that have the power to silence genes. The behavior of this entourage of molecules can be altered by the environment (or "nurture," to use the terminology of the classic "nature versus nurture" debate) and can have a profound effect on an individual's phenotype.

For instance, in normal, healthy mice, the agouti genes are kept in the "off" position by the epigenome, which attaches methyl groups to the corresponding regions of DNA, resulting in the DNA's compaction to prevent transcription. In yellow and/or obese mice, however, the same genes are not methylated; thus, these genes are expressed or "turned on." The turning on of this single gene results in an apparent freak of nature. Mice whose agouti gene is "on" are also more likely to suffer from diabetes and cancer as adults.

Environmental Triggers

A number of environmental triggers have been shown to affect the behavior of an organism's epigenome, tipping the balance between methylation or lack thereof, and thus between genes that are "off" and those that are "on." One suspected trigger is a chemical found in many plastic drink bottles, including baby bottles, called bisphenol A. In one particularly notable study, scientist Randy Jirtle and his group of researchers exposed pregnant mice to bisphenol A and watched as more of their genetically identical progeny developed into yellow, obese mice than would normally be expected (Dolinoy et al., 2007). In Jirtle's experiment, DNA methylation at the agouti gene sites was decreased by 31%. (DNA methylation was reduced on other genes as well.) These results supported the hypothesis that bisphenol A alters the action of organisms' epigenomes by removing methyl groups from DNA.

The implications of this discovery are staggering. With the rise of obesity in Americans coinciding with the widespread use of bisphenol A in everything from water bottles to dental sealants, one can't help wondering whether there is a causal connection. Yet, Jirtle himself is the first person to say that such an association cannot be definitively demonstrated until evidence shows that bisphenol A indeed affects the expression of the human genes involved in obesity.

So, how does the agouti gene cause such disparate effects in mice? It was first discovered that the agouti protein binds to a melanocortin receptor located on a mouse's skin cells, which blocks those cells from making black pigment (Lu et al., 1994). Thus, because the agouti gene is constantly turned "on" in mutant mice, the melanocortin receptor is always blocked, and the animals are yellow. Roger Cone speculated that the same type of receptor might also be present in a mouse's brain. In the same 1994 paper, he reported finding melanocortin receptors in an area of the mouse brain known to be involved in feeding behavior and body weight set point. Thus, the agouti protein appears responsible for both phenotypic differences in mouse twins: coat color and body weight.

But exactly how does exposure to bisphenol A affect both skin cells and brain cells? Through careful study, Jirtle found that the amount of DNA methylation was fairly consistent through an individual mouse's body. This result suggested that the demethylation that led to yellowness and obesity occurred in early development. Despite this suggestion, not all the mice pups that Jirtle observed grew to be unhealthy. In other words, bisphenol exposure didn't guarantee obesity in mice; rather, it simply increased the risk of developing obesity.

Environmental Protection

When gene expression goes awry during development, as in bisphenol-exposed mouse pups, the consequences can cause changes in adult mice that were not seen at birth. This phenomenon, called fetal programming, may play a role in many health conditions, including heart disease, diabetes, obesity, and cancer. The yellow agouti mouse has been a great animal model with which to study epigenetics and fetal programming. Recently, it has also been used to show that dietary factors can prevent the agouti gene from being turned on.

More specifically, not only did Jirtle's group find an increased risk of disease with maternal chemical exposure in mice, but they also noted that certain nutrients were protective. In particular, supplementing the mothers' diets with methyl-donating substances, such as folic acid and vitamin B12, was shown to counteract the reduction in DNA methylation caused by bisphenol A. In addition, a constituent of soy products called genistein prevented an increased number of unhealthy offspring. Whether a similar diet might reverse epigenetic effects once they appear, however, is unknown and awaits experimental testing. Despite such uncertainties, this epigenetic mechanism clearly demonstrates how profoundly environment can affect gene expression and phenotype in a long-lasting way.

References and Recommended Reading

Dolinoy, D. C., et al. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proceedings of the National Academy of Sciences 104, 13056-13061 (2007) doi:10.1073/pnas.0703739104

Duhl, D. M., et al. Neomorphic agouti mutations in obese yellow mice. Nature Genetics 8, 59-65 (1994) doi:10.1038/ng0994-59 (link to article)

Lu, D., et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371, 799-802 (1994) doi:10.1038/371799a0 (link to article)


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