Cleveland research team identifies biological mechanism that may explain obesity relapse

Two enduring biological mysteries have remained unsolved for decades: why almost everyone who loses weight gains it back, no matter how they lost it, and why obesity passes from mother to child at rates that diet and environment cannot explain. 

Now, scientists from Case Western Reserve University and Harrington Discovery Institute at University Hospitals have identified why.

In a recent study published in Cell Reports, researchers found that obesity creates a lasting biological change in fat cells that keeps the hunger hormone, asprosin, elevated (“obesity memory”)—even after weight loss. 

The findings may help explain why many people regain weight after dieting or discontinuing GLP-1 medications, and why obesity risk can persist across generations.

“Imagine having an appetite-stimulating signal stuck in the ‘on’ position day after day, despite losing weight,” said Atul Chopra, associate professor of medicine, genetics and genomics at Case Western Reserve School of Medicine, investigator and associate director of the Harrington Rare Disease Program at Harrington Discovery Institute at UH and the study’s senior author. “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.” 

The researchers also found that blocking the asprosin pathway in mouse models—from the gene that produces it to the receptor in the brain that responds to it—prevented both weight regain after dieting and inherited obesity risk. 

The finding points to new therapeutic strategies that could address the relapse problem drug companies are actively trying to solve.

“These patterns have been observed for decades, but nobody knew the exact molecular mechanism that makes obesity so persistent or how it transmits across generations,” Chopra said. “We wanted to find the biological basis for that persistence.”

The researchers initiated the study in search of what turns up the hunger hormone asprosin in obesity. They found that an inflammatory signal, called TGF-β1, does this. The biggest surprise was that a brief exposure to this signal created a lasting change that persisted for weeks after the signal was gone. 

“It was like flipping a light switch that stays on even after you remove your finger,” Chopra said. “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,” he said. “This same signal crosses the placenta and programs a baby's fat cells before birth.”

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. 

“We need to treat obesity as a condition that leaves lasting biological scars, not just a temporary state of excess weight,” he said. 

This explains why patients on GLP-1 medications regain weight when they discontinue the drugs. The medication suppresses appetite temporarily but does not erase the epigenetic memory in fat cells. 

Pharmaceutical companies are actively seeking ways to help people maintain weight loss after treatment. The new findings identify a potential complementary target: a pathway that may sustain the biological drive toward regain after weight reduction.

The study was designed to test its central observation beyond a single laboratory. A separate laboratory led by Seth Field, professor at Case Western Reserve School of Medicine and director of physician-scientist programs and chief scientific officer at the Harrington Discovery Institute at UH, reproduced the key persistence finding. Analyses of publicly available mouse and human datasets also yielded supporting evidence. 

While further human research is needed, the convergence across laboratories and datasets strengthens the case that the mechanism warrants serious investigation. 

The critical next step in this research is translating the findings to humans. The researchers plan to confirm that the same epigenetic memory operates in human fat tissue after weight loss, and test whether therapies that block asprosin or reset these epigenetic marks can prevent weight regain in people. 

“Given the need for durable obesity treatments, we are interested in whether asprosin-blocking therapies could be used alongside or after GLP-1 treatment to prevent rebound,” Chopra said.