Obesity appears to change genetic expression in ways that favor the development of diabetes and other conditions — changes that might even be passed on to the next generation.
Researchers are beginning to unlock the complicated interplay between obesity and its downstream morbidities by looking at changes it appears to be causing in gene expression. The emerging field of epigenetics is elucidating underlying mechanisms — and epigenetic drugs already in use for cancer treatment offer hope that similar drugs could be found for obesity and diabetes.
Genes control an organism’s phenotype, but outside forces can switch genes on and off. “Epigenetic mechanisms control how genes work,” says Rebecca A. Simmons, MD, professor of pediatrics at the University of Pennsylvania, Philadelphia.
Insulin production is a clear illustration of this idea, says Charlotte Ling, PhD, professor at Lund University Diabetes Centre in Sweden. Every cell contains the same DNA sequence, so every cell contains the gene for insulin production. “Yet insulin is only expressed in one cell type in the whole body, in the pancreatic beta cells. The body needs some kind of tool to regulate in which cell and when things will be expressed, and it can use epigenetic modifications to control this kind of cell-specific gene expression,” Ling says.
The field of epigenetics is so new that even the definition is in flux. The term was coined to refer to heritable changes that occur in gene expression without a change in the underlying DNA sequence, but has since been expanded to include other alterations in gene expression, particularly those that survive cell replication. Basically, chemical tags or marks can be attached to DNA that affect its expression, and the tags may be passed on to future generations.
One of the main epigenetic mechanisms receiving attention, particularly in relation to obesity and diabetes, is DNA methylation. In DNA methylation, methyl molecules bind to DNA, generally to cytosine. Methylation typically represses gene expression, so identical genes with different methylation patterns express differently. Researchers are trying to map this “methylome” portion of the epigenome to understand the changes involved.
Mapping the Methylome
A team of researchers from the U.S., U.K., and Sweden compared obese and lean mice and identified several hundred regions where methylation patterns differed. When the researchers compared fat cells from obese and lean humans, they found the same pattern of differences. “Mice and humans are separated by 50 million years of evolution, so it is interesting that obesity causes similar epigenetic changes to similar genes in both species,” says study lead author Andrew Feinberg, MD, MPH, director of the Center for Epigenetics at the Johns Hopkins University School of Medicine, Baltimore, Md.
The researchers found that many of the epigenetic changes associated with obesity affected genes known to raise diabetes risk. They also compared before and after samples from obese patients who had undergone gastric bypass and found that many of the obese-type methylation patterns reverted to lean-type patterns.
“Mice and humans are separated by 50 million years of evolution, so it is interesting that obesity causes similar epigenetic changes to similar genes in both species.” – Andrew Feinberg, MD, MPH, director, Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Md.
Ling and her team compared the methylome in pancreatic islets of healthy individuals and patients with type 2 diabetes. The analysis revealed epigenetic changes in about 800 genes in people with type 2 diabetes. More than 100 of these genes had altered expression, many of them in ways that could contribute to reduced insulin production.
In another study, Ling and colleagues looked at the methylation patterns of 14 pairs of identical twins, one healthy and one with type 2 diabetes. Although they found that the twins had similar methylation patterns in general, in the twins with diabetes the genes involved in inflammation were upregulated and those involved in fat and glucose metabolism were downregulated. The researchers believe that the differences are due to lifestyle.
Ling says that the methylation patterns marking diabetes could turn out to be useful early warning signs, for example, if the methylation patterns in target tissues could be reflected in blood. “Thereby, we can at an early stage identify people at risk for disease, and then try to be preventative,” she says.
Reversing Changes with Exercise
In a first of its kind study, Ling also investigated how exercise changes methyl groups in the fat cells. The study involved 23 slightly overweight, healthy men aged about 35 who had a low level of physical activity. For six months, the men attended aerobic exercise classes an average of twice a week, and showed improved fitness and weight loss without dietary changes.
In before and after cell samples, the researchers found changes in the methylation patterns in 7,000 genes, including beneficial changes in many genes linked to diabetes and obesity. The researchers confirmed the findings using in vitro studies of adipocytes in which they silenced some of the implicated genes, resulting in changes in insulin sensitivity and fat storage. “Our study shows positive effects of exercise, because it changes the epigenetic pattern of genes that affect fat storage in the body,” says Ling, who is speaking on epigenetic changes in patients with type 2 diabetes at ENDO 2016 in Boston in early April.
Obesity Heritability through Sperm?
Is it possible that some of these changes are heritable? Obesity runs in families, with the usual questions of nature vs. nurture, but some researchers are starting to believe that parents’ obesity itself (independent of their DNA) could affect a child’s epigenome. A study by Danish researchers in December in Cell Metabolism implicates an epigenetic mechanism in sperm that could potentially tend a child toward obesity. A comparison of the sperm of 13 normal weight subjects and 10 obese subjects showed a “distinct epigenome that characterizes human obesity” with distinguishing small noncoding RNA expression and DNA methylation patterns, particularly in genes controlling brain development and function.
The study also examined the sperm of morbidly obese men who underwent gastric bypass before the surgery and, a year later, after weight loss. They found “a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite” back toward the lean type.
“Everybody in the field is very excited about this study,” says Simmons. “But the question remains whether those changes can be transmitted to the offspring to result in a phenotype.” Simmons is cautious in interpreting many results, pointing to the perennial issue that association is not causation. Teasing out causes will take a lot more work. “We know that there are changes. We know that they can be reversed. But we don’t know how they influence the phenotype,” she says.
Cancer Drugs Already in Use
Epigenetic changes can drive the unrestrained cell growth that characterizes cancer cells by switching on or off genes involved in cell growth or switching off the immune response leading to a failure to destroy tumors. Armed with this knowledge, cancer researchers have developed a relatively new class of drugs targeted at another main epigenetic mechanism, histone modifications. Histone is the protein spool that DNA is wrapped around that plays a key role in DNA replication. The FDA has approved drugs designed to inhibit the activity of histone deacetylases for the treatment of cutaneous T cell lymphoma, pancreatic cancer, and multiple myeloma.
“We are at the stage where we are thinking about [epigenetic-based drugs] in the way that cancer researchers thought about it a few years ago. The tools to study it are rapidly emerging, and I think that we will probably have the answers in the next few years. We have mapped epigenetic changes in lots of populations, and now we need to understand what causes those changes.” – Rebecca A. Simmons, MD, professor of pediatrics, University of Pennsylvania, Philadelphia
A drug to treat glioblastoma, temozolomide, takes advantage of DNA methylation, killing cancer cells by adding methyl groups to their DNA.
These epigenetic-based drugs could serve as models for drugs for obesity or diabetes. “All the enzymes that are modifying our epigenome are potential targets for drugs,” says Ling.
“We are at the stage where we are thinking about this in the way that cancer researchers thought about it a few years ago,” says Simmons. “The tools to study it are rapidly emerging, and I think that we will probably have the answers in the next few years. We have mapped epigenetic changes in lots of populations, and now we need to understand what causes those changes.”
As this greater understanding emerges, the impact of epigenetic research will undoubtedly be felt.
— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about how biotin could affect thyroid tests in the January issue.