GLP-1 medications are marvels at melting off the pounds, but once you stop taking them, the weight comes back. It’s a dynamic that’s familiar, and frustrating, to anyone who’s tried to lose weight. Now a recent study published in Cell Reports may have uncovered the molecular mechanisms behind this vexing yo-yo effect (at least in mice).
Previous studies have shown mouse fat cells retain a kind of memory of obesity that’s epigenetically imprinted and persists through weight loss. According to this new study, led by a team of geneticists at Case Western University, transforming growth factor beta 1 (TGF-β1), a cytokine involved in inflammation, could be responsible for the rewiring. The team discovered that mouse adipose cells treated with the cellular signal increased their production of asprosin, a hormone that’s normally produced during fasting and stimulates the appetite.
Read more: “How Obesity Leads to Memory Loss”
In live animal models, mice who received TGF-β1 showed increased food intake that resulted in weight gain. Remarkably, only a brief exposure of TGF-β1 was necessary to produce effects that persisted for weeks. But when the researchers genetically removed both asprosin and its receptor, the treatment produced no effect. Zooming in to the genetic level, they discovered TGF-β1 remodeled the chromatin in adipose tissue, exposing the gene that produces the precursor to asprosin.
“Imagine having an appetite-stimulating signal stuck in the ‘on’ position day after day, despite losing weight,” explained study author Atul Chopra of Case Western in a statement. “Our findings suggest one reason weight regain can be so difficult to prevent after treatment ends.”
They could also help explain another mystery related to obesity: why it passes from mother to child at rates that can’t be determined by diet and environment. TGF-β1 can pass through the placenta, so the team mated female mice with artificially induced obesity to male mice with normal weights. Even though the resulting baby mice had normal TGF-β1 levels, they showed elevated asprosin levels.
Fat cells retaining a memory of obesity may sound bleak, but the team is hopeful it could also provide a vital therapeutic target for new drugs. “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.
Of course, the findings will need to be reproduced in humans, first. 
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