Anyone who has lost a lot of weight knows the cruel part can come later. The scale drops, clothes fit again, and the hard work seems to have paid off. Then the pounds begin creeping back, sometimes alongside an appetite that feels unusually hard to quiet. A new study in mice points to a physical reason that could help explain why.
Researchers found that obesity can leave a lasting mark on a single gene in fat cells. That mark keeps production of a hormone called asprosin running high even after the extra weight is gone. Asprosin, in turn, pushes the brain toward food.
The research, published in Cell Reports, also suggests the effect can begin before birth. More intriguingly, it identifies several places where future drugs might intervene.
The major unanswered question is whether the same molecular memory exists in people.
The Memory Lives In One Gene
Instead of a vague “epigenetic switch,” the research team traced the effect to one stretch of DNA that already has a day job.
That stretch is FBN1, the gene for fibrillin-1. Its last two exons also produce asprosin. During obesity, a signaling protein called TGF-β1 rises and switches the gene on in fat cells, causing them to make more asprosin.
What happened next is the important part. One brief spike of TGF-β1 was enough to reshape the chromatin around the gene into what the study callswhat the study calls an “open chromatin conformation.” Once opened, it stayed that way. As a result, output remained high after the mice lost weight and even after TGF-β1 returned to normal.
Chopra, quoted in Harrington’s release, said the switch stays flipped “for weeks” even after mice shed all their excess weight.
A Known Hormone With A New Explanation
Asprosin itself is not new. What scientists lacked was a reason it stays high.
Earlier studies found elevated asprosin in people and mice with obesity, with levels rising alongside BMI and severity. FBN1 activity is also higher in the fat tissue of obese women and tracks with the size of their fat cells.
Asprosin is released from white fat during fasting, and it has two notable jobs. It tells the liver to release glucose. It also tells the brain to go find food.
That appetite signal travels through a receptor called PTPRD on AgRP/NPY neurons in the hypothalamus. When mice lacked PTPRD only in those neurons, they stopped responding to asprosin’s appetite boost and were protected from diet-induced obesity.
That matters because it gives researchers something unusually specific: a defined brain circuit they may eventually be able to target.
Related: 8 Hard Truths About Weight Gain After 50
Why Appetite Drugs May Not Be Enough
Image Credit: sosiukin/123RF
If the memory outlasts the weight, a medication that works only while you take it leaves the underlying switch alone.
GLP-1 drugs suppress appetite during treatment, but they do not erase this kind of molecular memory. In the mouse research, disrupting the FBN1–asprosin–PTPRD pathway, either genetically or with drugs, prevented weight regain and the transfer of obesity risk to offspring.
The pathway offers several possible intervention points. A therapy could target TGF-β1 signaling upstream, the chromatin state at FBN1 in the middle, or asprosin and its receptor farther downstream. Antibodies against asprosin have already reduced body weight and food intake in obese mice in earlier research.
What happens alongside long-term GLP-1 treatment is less clear. Whether those drugs alter TGF-β1, FBN1 or asprosin in people remains unanswered. If they do not, durable weight maintenance could eventually require treatments that tackle more than one part of the biology.
The Risks Of Targeting This Pathway
Every point on that map comes with baggage.
TGF-β1 is involved in immune regulation, wound healing, and tissue remodeling, so blocking it throughout the body could create serious side effects.
FBN1 is not an easy target either. Mutations in the gene cause Marfan syndrome and related connective-tissue disorders, while the long-term consequences of changing its activity specifically in fat are unknown.
Then there is PTPRD. Its work extends well beyond appetite: the receptor also plays a role in neuronal development and function. Recent research has additionally linked it to tau pathology in Alzheimer’s disease.
In other words, the pathway may offer several drug targets, but none comes with a clean slate.
Other Memories May Be Involved Too
This may be one piece of a bigger puzzle.
The authors say public human datasets support the mechanism, but direct proof that it works the same way in people is still missing.
Meanwhile, other research suggests the body may hold onto more than one kind of obesity-related memory. A 2026 University of Birmingham study found that CD4+ T cells retain obesity-linked DNA methylation patterns for an estimated 5 to 10 years after weight loss. Earlier work has also found persistent changes in fat cells themselves.
Whether those memories operate independently, reinforce one another, or reflect different biological processes remains unknown. The next question is more immediate: after weight loss, do human fat cells show the same open chromatin at FBN1 seen in mice?
If your body could carry a molecular memory of past weight, would knowing that change how you approach keeping it off?
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