The United States is leading the international pandemic of obesity. Once a child becomes obese, it is incredibly difficult to sustainably return to a normal weight as an adult. Is obesity due to genetics or overeating? There is increasing evidence that obesity changes our genes making both us and our children more susceptible to obesity. The explanation is in the science of epigenetics.
What is epigenetics?
The concept that our environment can change our genes is “epigenetics”. Each person’s genes are composed of a fixed sequence of the four nucleotide bases: adenine, cytosine, guanine, and thymine in our DNA. These genes are “read” in the nucleus of cells and the reading of the genes determines how and when to make various proteins. These proteins determine everything from our bodily appearance to how our organs function. But environmental factors can affect the structure of genes and how these genes turn on and off. There are three main mechanisms by which our environment can change our genes:
- DNA methylation. A methyl group is a chemical structure that can be attached to our DNA. Adding a methyl group to a cytosine nucleotide is “methylation” which can turn on a gene. Removing a methyl group is “demethylation” which can turn off a gene. Our genes can become methylated or demethylated by various environmental factors such as chemicals, drugs, diet, and aging. Importantly, when a parent’s genes become methylated, their baby can inherit those methylated genes. In other words, our environment can change our offsprings’ DNA.
- Histone modification. Histones are proteins that wrap around DNA. When histones are packed tightly together on DNA, they can cover up genes, making them unreadable. By adding or removing chemical groups from histones, genes can be turned on or turned off.
- Non-coding RNA. The genes located in DNA tell our cells what kinds of proteins to make by creating mRNA (messenger RNA) molecules that function as the signal or template for ribosomes located in the cytoplasm of the cells to make those proteins. Some non-coding RNAs can inactivate mRNA thus short-circuiting the messages generated by our genes. In other words, the DNA sends out a signal to make a protein but the ribosomes never receive that signal.
Many different environmental factors can cause epigenetic effects resulting in disease. For example, smoking causes demethylation of the AHRR gene. Tuberculosis can cause increased histone aggregation that can turn off the IL-12B gene. DNA methylation of the BRCA1 gene can increase the risk of breast cancer.
One of the most famous examples of how epigenetics affects both people and their offspring was the Dutch famine of the winter of 1944-45. At the end of World War II, the Nazis blocked food to the Netherlands beginning in November 1944 until Allied liberation in May 1945. This resulted in a precipitous 6-month serious food shortage in the Netherlands and as a result, the typical caloric intake of Dutch citizens fell to 400-500 calories per day; 22,000 people died of hunger. The children of women who were pregnant during this famine had life-long health problems including a high rate of schizophrenia, heart disease, and type II diabetes compared to their siblings who were not in utero during the famine. Research 60 years after the famine found that these children (now older adults) had increased methylation of some genes and decreased methylation of other genes, indicating that when mothers were starved during pregnancy, their fetuses’ genes underwent methylation changes and these changes lasted the entire lifetime of the sons and daughters.
Epigenetics and obesity
Since 1975, the number of obese humans worldwide has tripled. Genetics alone does not explain why some people become obese and others do not. Studies have shown that genes linked to obesity such as the leptin, adiponectin, PGC1A, and insulin genes are regulated by methylation. There is growing evidence that obesity can cause DNA methylation. For example, researchers at the Medical College of Georgia reported in 2019 that in 1,485 subjects, obesity caused changes in DNA methylation that persisted over a 6.2 year period. It follows, therefore, that if a pregnant woman is obese, her child’s genes that regulate obesity can be altered and that alteration can persist for the child’s entire life.
For years, physicians’ recommendations for weight loss was straightforward: just take in fewer calories than you burn up. This led to a perception that obesity was simply due to the chosen behavior of the obese person – if they could just eat less and exercise more, they wouldn’t weigh so much. But many of my patients have told me that no matter how much they diet, they cannot lose weight. And those who do lose weight soon gain it back after a year or two. Epigenetics suggest that obesity is not simply due to a person making a conscious choice to eat too many calories and not exercise enough. Instead, it is due to changes in their genetic make-up.
The change to the majority of Americans now being overweight has resulted in a cultural normalization of obesity. But obesity comes with many health consequences that can reduce quality of life and reduce life expectancy. Obesity-related arthritis contributes to disability. Obesity-related diabetes contributes to heart disease. During the pandemic, COVID preferentially killed obese people. Just because everyone else is overweight doesn’t make being overweight right from a public health standpoint.
Epigenetic implications for reducing obesity
Another implication of the epigenetic basis of obesity is that we cannot just treat obese adults and we cannot just treat obese children who will later become obese adults. We need to think of obesity as a consequence of maternal conditions. If a woman is obese during pregnancy, then that woman’s child may be destined to become obese, regardless of the child’s diet after birth. In other words, the best predictor of whether a person will be obese as an adult may be whether or not that person’s mother was obese when she was pregnant.
Of even greater concern is that there is animal evidence that methylation of sperm and ova DNA can be passed on for multiple generations. If this is true with obesity, then it suggests that if your grandfather was obese because his DNA was methylated, then you are also more likely to be obese because you now carry that methylated DNA. If this is true, then the U.S. may be entering a vicious cycle of each generation getting more and more obese.
If our DNA can be methylated by environmental and nutritional factors, then it is likely that our DNA can also be demethylated with targeted therapeutic medications. By changing the direction of research into obesity treatments to focus on how we can pharmacologically manipulate DNA methylation of obesity-related genes, we may be able to develop more effective and more lasting treatments for obesity. The emerging field of genetic engineering could perhaps better be termed epigenetic engineering when applied to obesity treatment.
We should place a high priority for ensuring optimal maternal nutrition. The Dutch famine of 1944-45 shows us that maternal starvation is bad and recent research implies that maternal obesity is also bad. Both better nutritional education of women before pregnancy and better access to high quality nutrition before and during pregnancy are needed.
Because methylation of obesity genes early in childhood may persist throughout a person’s entire life, avoidance of excessive caloric intake by children is also critically important. The methylation research implies that once a person becomes obese, they are likely to remain obese. Prevention of obesity in childhood is likely to be more effective than treatment of obesity in adulthood.
What is the solution?
The new theoretic paradigm of obesity is that it is caused by (1) the amount of calories consumed, (2) the amount of calories burned, and (3) the modification of genes that regulate metabolism. Until we have effective ways of pharmacologically modifying methylation of obesity genes, we are left with the following tactics to reduce obesity in the U.S.:
- Increase caloric expenditure. Our country has an epidemic of exercise deficiency. There are many social and technologic reasons for this: a shift from a physical labor workforce to a skilled labor workforce, increased reliance on automobiles and mass transportation, and increased sedentary television and computer screen time. Judicious exercise during childhood and even during pregnancy is warranted.
- Decrease caloric consumption. During the past 75 years, the U.S. diet has shifted from home-prepared foods to highly processed foods. We have become increasingly reliant on fast food restaurants for a regular part of our diet. These are foods that are not only calorically dense, but they are also specifically taste engineered to make you want to eat more of them. Moreover, serving sizes have increased substantially in the past few decades. A major obstacle to weaning Americans off of fast food and highly processed food is that they are tasty, cheap, and convenient.
- Treat obesity earlier in life. Given that DNA methylation can last a lifetime, we need to aggressively treat obesity early – in childhood and perhaps even in parents prior to conception. In this sense, adult obesity is really a childhood disease and needs to be treated as such. This means more aggressive pharmacologic and bariatric surgery treatments of obese children.
What can hospitals do?
Our nation’s hospitals cannot cure the obesity epidemic by themselves but they can set the right examples. Our hospital cafeterias can serve food with correct serving sizes. We can eliminate high-calorie soft drinks containing sugar in our hospital vending machines. We can avoid leasing space to fast food restaurants with calorically dense menu items on our hospital campuses. We can provide and promote comprehensive weight management clinics.
As physicians, we need to be more proactive discussing obesity with our patients in a non-judgmental way. We need to identify children whose growth curves show weight percentiles that significantly exceed height percentiles. We can become more comfortable prescribing medications to lose weight, not only for our adult patients but also our pediatric patients. And we can become community educators and advocates for better nutrition and obesity prevention.
It turns out that obesity is a lot more complicated than we thought it was just a few years ago. The prevention and treatment of obesity is also a lot more complicated. But just because a problem is complicated does not mean we should just give up and accept it as the new normal. We have to take a more multi-faceted approach to obesity treatment and start that treatment earlier in life. We need to take back control of our own genes.
March 1, 2023