Researchers have identified a lasting biological change in fat cells that keeps hunger hormones elevated even after weight loss, offering a molecular explanation for why weight regain is so common after dieting or stopping GLP-1 medications—and how obesity risk can pass from mother to child.
According to the study, published in Cell Reports, researchers found that obesity triggers a lasting change in fat cells that keeps the hunger hormone asprosin elevated—a phenomenon the team calls "obesity memory."
The researchers traced the effect to an inflammatory signal called TGF-β1, which turns up asprosin production in obesity. They discovered that even a brief exposure to this signal created a lasting change that persisted for weeks after the signal was gone.
“Our findings suggest one reason weight regain can be so difficult to prevent after treatment ends. This same signal can also cross the placenta from mother to baby. The result is a child born with a programmed susceptibility to obesity. This may also explain why obesity became such an epidemic, and why the cycle has continued for generations,” said Atul Chopra, MD, senior author of the study, investigator and associate director of the Harrington Rare Disease Program at University Hospitals.
The study data also showed that blocking the asprosin pathway in mice prevented both weight regain after dieting and the transmission of obesity risk to offspring. This points to new therapeutic strategies that could address the relapse problem drug companies are actively trying to solve.
“Imagine having an appetite-stimulating signal stuck in the 'on' position day after day, despite losing weight,” said Chopra. “It was like flipping a light switch that stays on even after you remove your finger. Even after mice lost all the excess weight and TGF-β1 returned to normal, this switch in their fat cells remained flipped, keeping asprosin and appetite elevated. This gives us a molecular explanation for why GLP-1 drugs, which suppress appetite while you take them, cannot fix the underlying biological memory that drives hunger back up once treatment ends.”
Chopra said the key message for clinicians is that obesity relapse is not a failure of willpower or discipline. It is driven by a durable biological memory written into fat tissue that sustains hunger long after the pounds come off.
The team's next step is confirming that the same epigenetic memory operates in human fat tissue after weight loss, and testing whether therapies that block asprosin or reset these epigenetic marks could prevent weight regain in people, potentially alongside existing GLP-1 treatments.
Data from University Hospitals Cleveland Medical Center