Researchers have long puzzled over why people who diet or take weight-loss drugs are quick to regain weight after they stop. A new study has proposed a potential clue: a chemical mechanism that may encourage fat cells to continue making a hormone that makes us hungry and create a “memory” of obesity even after weight loss.
Scientists caution that the study’s evidence involves mice and is not proof of the mechanisms that explains weight regain. But it’s a step forward in a growing understanding of the cellular functions and changes underlying obesity, experts said. Recent studies have challenged the idea that inactivity is the main cause of obesity and identified other genetic factors, such as impaired GLP-1 production, associated with some types of obesity.
As weight-loss drugs become more popular, understanding why their effects can wear off so quickly once people stop taking the medications is becoming more important, the study’s authors said. Beyond losing weight, the researchers said, treating obesity could require tackling a “biological memory” in our cells.
“If we understand where that memory is coming from, maybe eventually we’ll have some way to stop that,” said Seth Field, a professor of medicine in endocrinology at Case Western Reserve University and an author of the study published September in Cell Reports.
The idea that cells can carry a memory of obesity is not new but researchers are still trying to understand the mechanisms of how it influences weight regain. Through epigenetics, scientists are examining how external factors can affect how our cells behave by altering chemical markers which can turn genes — and certain cellular functions — on and off.
A study in 2024 examined how obesity can cause epigenetic changes. It suggested that fat cells in both humans and mice retain lasting epigenetic changes after weight loss.
Mice with these cellular differences quickly regained weight, but researchers did not have a definitive answer to explain why.
The September study focused on epigenetic changes that affect the production of an appetite-stimulating hormone, asprosin. Researchers found that mice that were made to gain weight gained high levels of asprosin that lingered even after they lost weight.
“Their hunger is stuck in the on position,” said Atul Chopra, an associate professor of medicine and genetics and genomics at Case Western Reserve University and an author of the study.
The reason asprosin lingers in the body could be tied to the way a chemical messenger acts on fat cells, according to Chopra’s team. The chemical, TGF-β1, is associated with inflammation and elevated during obesity. It stimulates the production of asprosin.
TGF-β1 normally decays in minutes, but researchers discovered that its appetite-stimulating effect can last for much longer. A student in Chopra’s lab mistakenly left fat cells previously treated with TGF-β1 in an incubator; two weeks later, the cells still had elevated levels of asprosin.
When researchers injected TGF-β1 into mice, the mice still displayed elevated levels of asprosin weeks later, according to the study. Follow-up tests found that mice fed high fat diets, which naturally increased their TGF-β1 and asprosin levels, retained high asprosin levels even after losing weight.
“This mouse has a memory of prior obesity,” Chopra said. “‘I used to be obese. I’m not obese anymore, but I’d like to go back to that body weight.’”
It’s too early to apply the work conducted on mice to people. But Chopra said the role of TGF-β1 could provide a target for drug development and further research for humans.
“People who have lost a bunch of weight, look at their asprosin levels in their blood, and are they stuck in the ‘on’ position, just like we found in mice?” Chopra said. “And subsequently, can we wipe the memory [of the cells with elevated asprosin]?”
Claude Bouchard, a professor emeritus at Louisiana State University and a longtime researcher in genetics and obesity, praised the study, but added that hundreds of genetic traits have been associated with risk factors for obesity and more research would be needed to determine how important TGF-β1 is in humans.
“In most cases, it’s a constellation of those [genetic] traits that determine your risk,” Bouchard said.
Chopra said that, for now, the main takeaway for patients and physicians from obesity research should be that managing the condition is not just a matter of willpower or personal behavior.
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