Primary care physicians (PCPs), a suggestion: The next time a patient with obesity walks into your clinic, look past the weight and instead consider how certain elements in that person’s environment, past and present, helped create that patient’s condition.

And now consider whether that patient, male or female, is a parent, or intends to be, because without intervention, that patient’s child, and that child’s future offspring, will likely become another datapoint in the obesity pandemic.

This situation exists because of epigenetic transgenerational inheritance. With continued exposure to the offending environment, the susceptibility to obesity and its comorbidities will threaten future generations. And disease types will multiply.

For susceptible individuals — at least 60% of those with obesity are affected — the societal, cultural, and even political lure to reach the disease state of obesity is a constant presence. Humans alone among earth’s species bestow reasons to eat beyond survival: business lunches. Birthday parties. Holiday spreads. Snacks used to comfort and/or gain obedience.

If it’s a pregnant woman with overweight partaking in these less than healthy spreads, look out because it is these early-life exposures that can affect stem cells and cell differentiation, thereby increasing the unborn child’s susceptibility to altered transcriptomes, affecting disease etiology and phenotypic variation.

Obesity not just is a high BMI, said Stephen Cook, MD, MPH, associate professor, University of Rochester Medical Center in Rochester, New York, but also has biological drivers, such as whether the mother gains weight during pregnancy, if the baby is too small for their gestational age, whether the mother or child had adverse childhood experiences, and so much more — such as lack of sleep.

“What happens during pregnancy plays a huge role,” said Mahua Choudhury, PhD, professor of pharmaceutical sciences and co-director of Center for Microencapsulation and Drug Delivery at Texas A&M University in College Station.

In rat studies, the lab of Michael K. Skinner, PhD, Center for Reproductive Biology and School of Biological Sciences, Washington State University, Pullman, has shown that descendants of animals with epigenetic alterations not only inherit the alterations but also have increased incidence of disease pathology. His lab extended the subject animals 20 generations, and the disease rate among these animals was 90%. At this point, “the population started to collapse, [and] they couldn’t reproduce,” Skinner said in an interview.

But the beauty of a gene altered by epigenetics is that it can be reversed, said Choudhury, if the stage before the gene alteration can be identified, something that her lab is looking at now.

If those epigenetic shifts remain unchanged, however, those changes might become part of the DNA code. “We are changing our evolution direction now. Those who survive will have a different molecular makeup,” Skinner said.

“We often see obesity traveling in families,” said Amanda Staiano, PhD, director, Pediatric Obesity and Health Behavior Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge. From a data perspective, “the [population’s] normal distribution has skewed toward obesity.”

In July, Cook, Staiano, and colleagues published a pragmatic trial in JAMA Pediatrics showing that intense education of a parent and child using behavioral therapy, nutrition counseling, and more in family practices and pediatric primary care clinics could start to undo the damage. The study crossed four states and included 700 children and their parents. The point, said Staiano, was to see if families could learn to get on a healthy lifestyle track from those places where they already go for care.

Choudhury said such a holistic approach is valuable. PCPs, she said, are an important part of the community. Their job is dedicated to seeing patients, but their involvement in these studies is warranted because, she said, “something is adapting.” 

Epigenetics

In the 21 years since Science published the Skinner lab’s landmark study showing that noncoded information, via an altered germline, can be passed down to progeny, researchers have found that noncoded information can regulate traits; processes; and responses such as physical appearance, energy metabolism, behavior, and longevity. The 2005 study looked at fungicide inheritance.

“The fact that it would be epigenetic inheritance was way outside the box,” Skinner said. “We repeated that experiment 100 times on 20, 30 different environmental exposures. Then other [researchers] did the same thing.” 

The fact that 50% of the world’s population has obesity “is not a minor thing,” he said; in 1950, that rate was 5%. People have this susceptibility, and each generation has increased disease frequency and higher fat depositions than would normally occur.

Epigenetics and genetics are intricately linked, he said. All genetic mutations have a precursor that is epigenetically caused. “Epigenetics has a significant role, if not the role, in promoting these genetic mutations.” 

Genetics, said Gitanjali Srivastava, MD, professor of medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, “remains one of the most misunderstood aspects of obesity, despite decades of evidence demonstrating that obesity risk is substantially heritable.” 

Choudhury, working with pregnant mice, found in 2022 that just one long noncoding RNA can regulate sirtuins, an epigenetic modulator class that regulates metabolic pathways, after the mice had a 6-week, high-fat, high-fructose diet. Their male offspring had even more epigenetic changes. “The changes can happen quickly, especially the epigenetic ones,” said Choudhury. New, noncoding RNA that are part of epigenetic modification “can lead to more permanent changes and lead to disease, like obesity and type 2 diabetes,” she said.

Trying to Change the Future

There’s a lot to change.

The CDC says 21% of America’s youth, aged 2-19 years, have obesity; the largest percentage, at 23%, are those aged 12-19 years. Staiano said that 80% of children with obesity will stay that way as adults. And that road to excess weight can start with an infant’s formula. A Pennington colleague, Staiano said, told her that preparing a bottle for an infant by rounding a scoop of formula, as opposed to leveling it, is adding a significant amount of calories.

The JAMA study started in 2019; when the pandemic hit, “telehealth saved us,” said Cook. The children were aged 6-15 years; more than 100 family physicians and pediatricians were trained. Those in the treatment group had access to lifestyle coaches, social workers, and licensed family therapists. The others received regular care.

“This was a parenting intervention more than anything,” said Cook.

The social workers were “awesome,” he said. They taught parents about environmental controls, sleep and activity schedules, dealing with bullying, planning for meals on vacation, etc. One surveyed parent’s response: None of my kids fight with me about going to bed anymore.

The trial’s results: At baseline, children in both groups were 77% above a healthy weight. By the 6-month follow-up, 42% of those who received the intervention lost enough weight connected with better heart and metabolic health, roughly 1.5 times the rate of the other children. Both groups continued to lose weight after 1 year. And the parents in each group lost weight; those in the intense treatment group lost a bit more.

The researchers sought help in easing the financial burden on the clinics. Staiano said one of the trial’s funders, Louisiana Blue — yes, an insurance company — sent out representatives to show the clinics how to bill for the embedded services. Her group has done the same with hospitals to get billing codes for Medicare and healthcare plans and helped with training staff or hiring.

Recruiting physicians for the JAMA study was difficult, Staiano said, mainly because of the burden that it put on the physicians’ clinics. Her efforts have paid off: In 1 week, 170 pediatricians have sent referrals to Pennington for a new family-focused study that’s in the works. “We are changing the way workflow goes.” 

The family focus works in his clinic as well, Srivastava said. He asks patients about those with large bodies in their families and asks to see family photos that are on their phones.

“Looking across generations often reveals striking patterns of body composition and fat distribution,” he said. “We discuss whether obesity, central adiposity, diabetes, cardiovascular disease, or other metabolic conditions appear to cluster within families. These conversations help patients recognize obesity as a biologic and familial condition rather than a personal failure.”

Srivastava declared receiving advisory fees from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Quest Diagnostics, and Madrigal. Cook reported receiving grants from Patient-Centered Outcomes Research Institute (PCORI) for a study. Staiano reported receiving grants from PCORI, Louisiana Blue, Louisiana Healthcare Connections, and the National Institutes of Health for a study. The others reported no disclosures.