Low-calorie diet induces beneficial changes in the DNA of obese women

After six weeks of a low-calorie diet, the pattern of gene expression in obese women became more similar to that of non-obese women in the same age group. Genes associated with cancer became less active.

By André Julião  |  Agência FAPESP – A study conducted by researchers in Brazil and Spain shows that obese women who follow a low-calorie diet may not only lose weight but also bring about biochemical changes in their DNA that reverse their propensity to certain kinds of cancer. An article reporting the findings is published in the European Journal of Clinical Nutrition.

The research was part of a project funded by FAPESP to analyze DNA methylation patterns in obese patients submitted to bariatric surgery with and without a physical exercise regimen or diet. 

DNA methylation is a biochemical process whereby a methyl group, comprising one carbon and three hydrogen atoms, is added to the cytosine base of the DNA molecule, potentially altering the expression of certain genes. Some DNA methylation patterns may foster or inhibit the development of diseases.

“The main finding of the study is that people with and without obesity have different DNA methylation profiles in specific genes, and this can be modified by weight loss. Depending on the intervention [surgery alone, surgery with exercise, or surgery with diet], different pathways are modified. The pattern doesn’t necessarily return to being the one seen in a person with normal weight,” said Carolina Nicoletti, first author of the article. 

Nicoletti is a researcher at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil. She conducted part of the analysis during a postdoctoral internship, also funded by FAPESP, for which her supervisor was Carla Barbosa Nonino, principal investigator for the project and FMRP-USP’s Nutrigenomics Research Laboratory (LEN).

“The growing prevalence and incidence of obesity and associated comorbidities are currently among the main public health problems. Obesity is a complex multifactorial disease, and a better grasp of the molecular mechanisms underlying the interactions among lifestyle, environment and genetics is vital to the development of effective strategies for its prevention and treatment,” Nonino said.

The researchers analyzed blood samples from 11 women with severe obesity. Their ages ranged from 21 to 50. The blood samples were collected before and after a six-week dietary intervention, which took place while they were in the Metabolic Unit of FMRP-USP’s hospital. There they were fed a diet with 1,800 kcal on day one, 1,500 kcal on day two, and 1,200 kcal per day for the rest of the period. They were monitored by a team of physicians, nurses and nutritionists, who ensured that they followed the diet correctly. In addition, the volunteers were asked not to alter the amount of daily physical activity they performed before the intervention.

Risk reduction

At the end of the six-week period, the volunteers had lost 1.8% of their weight or roughly 1 kg per week. “That may not seem a lot compared with bariatric surgery, but it’s a significant loss. In the case of people who weigh 150 kg and need to lose 50 kg, we must bear in mind that the change won’t happen in two months, but will probably take a year,” Nicoletti said.

The DNA methylation profile was studied using a tool capable of analyzing 500,000 regions simultaneously. The researchers analyzed patterns for obese women before and after the intervention, and compared them with the controls, comprising non-obese women in the same age group.

Before the intervention, the analysis found differences in 1,342 genomic regions and 953 genes in women both with and without obesity. More than 80% of the regions were hypermethylated in the control group.

When the researchers compared DNA methylation in obese women before and after the intervention, they found alterations in 16,064 genomic regions and 9,236 genes. Methylation levels were reduced by 16% in most of the regions. Genes involved in breast and colorectal cancer, such as SULF2, GAL and SNORD2, were 35% less methylated after the intervention.

“Many of these are pro-oncogenes, involved in cell survival and associated with the development of cancer,” Nicoletti explained. “They were less methylated in the obese women, meaning they were more expressed, favoring the formation of tumors. The changes that occurred after the dietary intervention suggests a reduction in the risk of cancer in these people.”

Despite the improvement, the intervention did not bring about identical methylation profiles in the two groups. However, the researchers believe continuing weight loss could do so.

The group will now analyze DNA methylation in patients submitted to bariatric surgery and an exercise regimen. The set of studies can contribute to an understanding of obesity, cancer, and the relationship between them.

The article “DNA methylation pattern changes following a short-term hypocaloric diet in women with obesity” is at: www.nature.com/articles/s41430-020-0660-1.