The cause of weight regain: ‘fat-cell memory’ keeps appetite signals on even after weight loss

A study has found that the cause of the “yo-yo effect,” in which people regain weight after losing it, may be a kind of “obesity memory” that remains in fat cells.

According to an Azure Life Science report on the 11th (local time), researchers at Case Western Reserve University and the Harrington Discovery Institute at University Hospitals reported in the journal Cell Reports that obesity leaves lasting biological changes in fat cells, keeping levels of the appetite hormone asprosin elevated.

The researchers said this “obesity memory” explains why weight returns after people stop dieting or taking GLP-1 drugs for obesity, as well as why obesity risk can be passed down across generations.

Atul Chopra, the study’s senior author and an associate professor of medicine, genetics and genome sciences at Case Western Reserve University, said, “The appetite-stimulating signal remains ‘on’ despite weight loss.” He added, “This signal can also be transmitted from mother to baby through the placenta.”

The researchers found that the inflammatory signal TGF-β1 is what raises asprosin levels in obesity. A key finding was that even brief exposure to this signal caused changes that persisted for weeks after the signal disappeared.

“It’s like a light switch that stays on even after you take your finger off it,” Chopra said. “Even after the mice lost all their excess weight and TGF-β1 returned to normal, the switch in their fat cells remained on, keeping asprosin levels and appetite elevated.”

The researchers said that in mouse experiments, blocking this pathway—from the gene that produces asprosin to its receptor in the brain—prevented both weight regain after dieting and inherited obesity risk.

The researchers said the findings could offer clues to new treatment strategies for addressing weight regain, a problem pharmaceutical companies are trying to solve.

“GLP-1 drugs suppress appetite while people are taking them, but they don’t correct the underlying biological memory that brings hunger back once treatment ends,” Chopra said. “We need to treat obesity not as a temporary state of excess weight, but as a disease that leaves lasting biological traces.”

The key findings were reproduced in a separate laboratory led by Seth J. Field, extending the work beyond a single lab, and analyses of publicly available mouse and human data also provided supporting evidence.

The researchers plan to determine whether the same epigenetic memory operates in human fat tissue and to test whether treatments that block asprosin or reset this memory can prevent weight regain.

“Given the need for ongoing obesity treatment, I’m interested in whether asprosin-blocking therapy could be used alongside GLP-1 treatment or afterward to prevent rebound,” Chopra said.