Fat tissue may retain a "memory" of obesity and increase weight regain after weight loss.

Scientists have discovered a molecular mechanism that may help explain why the body remains more susceptible to weight regain after weight loss. In a study published in the journal Cell Reports, the authors demonstrated in mouse models that obesity can leave a lasting molecular imprint on fat cells: the cytokine transforming growth factor beta-1, which is elevated during obesity, alters the regulation of the Fbn1 gene, resulting in elevated production of the appetite-stimulating hormone asprosin even after weight normalization.

Researchers call this phenomenon a kind of "memory" in adipose tissue. This isn't memory in the traditional sense, but rather persistent changes in gene activity. After a brief exposure to elevated transforming growth factor beta-1, the chromatin structure in the Fbn1 gene region changed such that this gene continued to function more actively even after the initial signal disappeared. As a result, asprosin concentrations in the blood remained elevated.

In mouse experiments, this persistent hormonal imbalance had functional consequences: the animals ate more and regained lost weight more easily. When the researchers genetically or pharmacologically interfered with the Fbn1-asprosin-Ptprd signaling pathway, the tendency to regain weight was reduced. This makes the discovered mechanism a potential target for future methods of maintaining weight loss achieved after treatment.

The second result of the study was even more unusual. Maternal exposure to elevated transforming growth factor beta-1 during pregnancy programmed the offspring's adipose tissue. The offspring retained elevated Fbn1 activity, had elevated asprosin levels, and were more susceptible to developing obesity when fed a diet conducive to weight gain. However, this result has so far been obtained primarily in preclinical models and does not allow us to conclude that the same mechanism has been proven in humans.

Main result	What was discovered?
Obesity increases transforming growth factor beta-1	This signal activates Fbn1 in fat cells.
Persistent chromatin changes occur	Fbn1 remains active even after the initial signal disappears
Asprosin increases	The hormone enhances signals that stimulate food intake.
After losing weight, the effect remains	Mice were more likely to regain weight
Exposure during pregnancy	The offspring became more susceptible to obesity
Blocking the signal chain	Prevented or attenuated both effects in experimental models

How fat tissue can "remember" previous obesity

The researchers focused on transforming growth factor beta-1, a signaling protein involved in inflammation, tissue remodeling, and gene regulation. Its concentration in adipose tissue can increase in obesity. The authors of the new study found that this signal can enhance transcription of the Fbn1 gene in adipocytes, the cells that make up a significant portion of adipose tissue.

Fbn1 encodes fibrillin-1, a large protein in the extracellular matrix. This gene is also of interest to obesity researchers because the hormone asprosin is produced from Fbn1. Asprosin enters the bloodstream and can affect the brain, specifically the hypothalamic neurons involved in hunger regulation. Therefore, increased Fbn1 activity can directly alter not only the properties of adipose tissue but also eating behavior.

A key observation of the new study was that increased Fbn1 activity did not necessarily cease immediately after the reduction of transforming growth factor beta-1. Even short-term exposure to this cytokine led to chromatin reorganization in the Fbn1 region. Chromatin is a complex of DNA and associated proteins whose organization determines how easily a cell can read a given gene.

Thus, after an episode of obesity, the cell could maintain a molecular state that promotes increased Fbn1 expression. The authors interpret this as transcriptional or epigenetic memory. An important difference between this mechanism and a typical transient hormonal signal is its persistence: body weight and transforming growth factor beta-1 levels can return to baseline, while increased Fbn1 activity and asprosin levels persist longer.

Stage	What's happening
Development of obesity	In adipose tissue, the influence of transforming growth factor beta-1 increases
Effect on adipocytes	Fbn1 transcription is enhanced
Chromatin reorganization	The Fbn1 region transitions to a more stable active state
Weight loss	Transforming growth factor beta-1 may be normalized
After losing weight	Fbn1 activity remains elevated
Consequence	The blood maintains an elevated concentration of asprosin

Why Asprosin May Promote Weight Gain

Asprosin is a hormone involved in energy metabolism and the regulation of feeding behavior. Previous studies have shown that it acts on specialized neurons in the arcuate nucleus of the hypothalamus that contain agouti-related peptide. These cells represent one of the key neural mechanisms that enhance hunger: when activated, the likelihood of food seeking and consumption increases.

One of the receptors through which asprosin transmits this signal is the protein Ptprd, or receptor protein tyrosine phosphatase delta. Asprosin has previously been shown to bind to Ptprd on the corresponding neurons in the hypothalamus. In experimental animals, deletion of this receptor made neurons significantly less sensitive to asprosin, reduced appetite, and increased resistance to obesity during a high-calorie diet.

The new study combines these observations with changes occurring directly in adipose tissue. A potential sequence of events emerges: obesity increases transforming growth factor beta-1, which alters the state of Fbn1 in adipocytes, increasing asprosin production, and asprosin, via Ptprd, enhances the activity of hunger-related neural circuits. Even after weight loss, the first part of this circuit may remain partially activated.

From a physiological perspective, this is particularly interesting because after weight loss, the body already has to contend with a whole host of adaptations that help restore energy reserves. Energy expenditure changes, hunger signals may be enhanced, and some satiety signals may be weakened. The discovered mechanism doesn't replace these known explanations and is likely just one of several factors, but it does demonstrate that adipose tissue itself may actively contribute to the long-term tendency to regain weight.

Component	Role in the proposed mechanism
Fat cell	Source of stable change in Fbn1
Fbn1	Gene associated with the formation of the asprosin precursor
Asprosin	A hormone that can increase hunger
Ptprd	Asprosin receptor in appetite-regulating neurons
Hypothalamus	One of the main centers for the regulation of eating behavior
Increased appetite	Helps restore lost body weight

Experiments have shown a link to weight gain

To test whether the discovered molecular memory actually has consequences for body weight, the authors used mouse models of obesity and subsequent weight loss. After a period of increased body weight, the animals were returned to conditions that facilitated weight loss. While transforming growth factor beta-1 concentrations returned to normal over time, the changes in Fbn1 and asprosin did not completely disappear. This persistence was crucial to the authors' hypothesis.

After weight loss, animals with persistently elevated asprosin levels consumed more food and regained the weight more easily. Thus, the researchers obtained not only a molecular marker of previous obesity but also an observable physiological consequence. According to the authors, this indicates that adipose tissue "memory" may play a role in post-weight loss behavior.

Of particular significance is the experiment involving interference with this pathway. The scientists targeted various links in the Fbn1-asprosin-Ptprd system using genetic and pharmacological approaches. Disruption of this signaling pathway prevented the characteristic weight regain, strengthening the argument for a causal, rather than merely statistical, link between the asprosin system and the observed effect.

Furthermore, an independent research team was able to reproduce the key stability of the molecular effect. The authors also examined available datasets obtained in animals and humans and found results consistent with the proposed model. However, the researchers emphasize that the crucial next step is direct confirmation of the existence of similar long-term epigenetic memory in human adipose tissue after obesity treatment.

Experimental question	Result
Does the molecular signal disappear after weight loss?	Incomplete: Fbn1 activity and asprosin remained elevated
Does this affect behavior?	Animals' food consumption increased
Is this related to weight gain?	Elevated asprosin promoted weight regain
Is it possible to disrupt the mechanism?	Yes, interference with the Fbn1-asprosin-Ptprd pathway prevented the effect
Was the result independently verified?	The key stability of the effect was reproduced by another laboratory
Has this been proven in humans?	Not yet, special studies are needed

The same system can program a tendency toward obesity in offspring.

The second part of the study focused on the intergenerational effect. It's known that children of obese women are statistically more likely to be overweight themselves, but this association cannot be explained solely by genetics or family eating habits. The authors decided to test whether the signaling system they discovered could influence the formation of adipose tissue even before birth.

In a mouse model, increased exposure to transforming growth factor beta-1 during pregnancy affected the developing offspring. After birth, these animals exhibited higher Fbn1 activity in adipose tissue and elevated asprosin levels. This molecular profile resembled the condition the researchers observed in adult animals after obesity.

Under normal conditions, this did not necessarily translate into the immediate development of severe obesity. The differences were particularly pronounced after subsequent exposure to a diet that promoted weight gain: the programmed animals proved more susceptible to obesity. This result is consistent with the concept of developmental programming, in which exposure during a critical period of intrauterine life alters the body's response to environmental conditions months or years later.

The most compelling part of the experiment was again the mechanistic intervention. Genetic or pharmacological disruption of the Fbn1-asprosin-Ptprd signaling system prevented the increased obesity predisposition of the offspring. This led the authors to suggest that the asprosin system may be one of the molecular mediators linking maternal metabolic state with future body weight regulation in the offspring.

Period	Change	Possible consequence
Pregnancy	Increased exposure to transforming growth factor beta-1	Programming developing adipose tissue
After birth	Increased Fbn1 activity	Increased formation of asprosin
Blood of the offspring	Higher asprosin	A more pronounced appetite-stimulating signal
Subsequent caloric nutrition	Increased sensitivity to metabolic stress	Higher tendency to obesity
Blocking the signal chain	Weakening of the action of the asprosin system	Protection against increased susceptibility in the experiment

Could this explain the weight gain after stopping weight loss medications?

The results are particularly interesting given the widespread use of glucagon-like peptide-1 receptor agonists and similar drugs. These medications significantly reduce appetite and enable many people to achieve significant weight loss. However, after discontinuing therapy, a significant proportion of patients experience weight regain, making maintaining the results a central challenge in modern obesity therapy. The authors of the new study consider the asprosin mechanism as a possible contributor to this process.

The proposed model is that while current treatments can effectively suppress appetite and promote weight loss, they do not necessarily reverse the molecular changes left in adipose tissue after a period of obesity. If Fbn1 activity and asprosin production persist, this internal signal may again promote increased food intake after external appetite suppression is discontinued. This is a biologically plausible hypothesis, but the study itself does not constitute a clinical trial of the drugs in humans.

The authors therefore consider asprosin blocking as a possible adjunctive strategy. In the future, such treatment could theoretically be used after weight loss or concurrently with primary anti-obesity therapy to reduce the likelihood of weight regain. Senior study author Atul Chopra stated that the team intends to study whether asprosin-blocking agents can be used in conjunction with or after glucagon-like peptide-1-based therapy.

However, the current study does not yet suggest that asprosin is a proven cause of weight regain in patients after discontinuing such medications. The study is primarily preclinical, and most of the causal experiments were conducted on mice. To translate this into clinical practice, it will be necessary to demonstrate the presence of a similar mechanism in humans, determine its contribution relative to other bodily adaptations, and test the safety of long-term interventions with the asprosin system.

Question	What can be said now?
Can Asprosin Promote Weight Gain?	Yes, this has been shown in mouse models.
Was discontinuation of GLP-1 therapy tested in this study?	The work is not a clinical trial of such a scenario in humans.
Could blocking asprosin be a cure?	This is a potential strategy that requires further research.
Can there be residual "memory" after losing weight?	In experimental models it was preserved
Can this data be used in a clinic?	No, clinical effectiveness has not yet been proven.

Why Results Are Important, But Can't Be Overstated

One of the most important ideas of the study is that obesity can leave behind persistent changes even after body weight has been normalized. This is consistent with the modern concept of obesity as a chronic disease with distinct biological mechanisms of maintenance. After weight loss, the body does not necessarily return to the state of a person who was never obese: certain hormonal, neural, and cellular adaptations can persist for a long time. The new study adds to this picture the possible epigenetic memory of adipocytes.

However, the asprosin system is unlikely to be the sole explanation for weight regain. Body weight is regulated by a complex network of signals between the brain, gut, adipose tissue, liver, and other organs. After weight loss, energy expenditure, the concentrations of several hunger and satiety hormones, the brain's response to food stimuli, and behavior all change. Therefore, it is more accurate to talk about a new potential component of this system rather than identifying a single cause of weight regain.

Results regarding offspring should be interpreted with equal caution. The study demonstrates the possibility of programming susceptibility to obesity through a signaling mechanism during pregnancy in mice. This does not mean that obesity is literally "passed on" to the child via a single hormone or that future body weight is predetermined by the mother's condition. Genetics, nutrition, physical activity, social environment, and many other factors continue to play a significant role.

Another factor to consider when evaluating a paper is the authors' declared commercial interests. Senior author Atul Chopra is listed as a co-author of patents related to asprosin, as well as a co-founder and stakeholder in companies working with related intellectual property. Such interests do not invalidate the results, but they do increase the importance of independent replication of the experiments and future research by other research teams.

What the study shows	What it doesn't prove yet
Mice's fat tissue may retain molecular memory of obesity	That an identical mechanism determines weight gain in all people
TGF-β1 is able to consistently alter Fbn1 regulation	That this is the only reason for weight gain
Elevated asprosin promotes overeating and weight regain in mice	That asprosin blockers are already effective and safe for patients
Maternal signal influences offspring susceptibility to obesity in animals	That maternal obesity inevitably causes obesity in the child
Breaking the signal chain prevents the effect in the experiment	That this approach is already ready for clinical use

What will be researched next?

The main task now will be to verify whether the discovered epigenetic memory exists in human adipose tissue. This will require comparing human adipocyte samples before and after sustained weight loss and determining whether chromatin changes in the FBN1 region persist alongside increased asprosin production. Only such data will allow us to understand the applicability of the mouse model results to humans.

The next question is how much this system influences the actual risk of weight regain. Even if molecular memory exists in humans, it can only explain part of the observed effect. It will be necessary to determine whether asprosin concentrations and FBN1 status correlate with who maintains weight loss after weight loss and who regains a significant portion of the lost weight.

A separate area of research involves developing methods to block asprosin or its interaction with Ptprd. Previous studies have already shown that removing Ptprd from appetite-regulating neurons or binding to circulating asprosin can reduce food intake in experimental animals. This new study expands the potential application of such interventions: they may be useful not only for initial weight loss but also for preventing relapse.

Finally, it will be necessary to determine whether it is possible to directly "erase" the fat cell's pathological epigenetic memory, rather than simply blocking the final hormonal signal. If FBN1 regulation can be safely restored to its original state, this could theoretically address one of the causes of long-term elevated asprosin levels. While this remains a research hypothesis for now, it is precisely this that makes the new study particularly interesting for the search for long-term treatments for obesity.

The next stage of research	Why is it needed?
Analysis of adipose tissue of people after weight loss	Confirm the presence of epigenetic memory of FBN1
Long-term monitoring of patients	To investigate the link between asprosin and weight regain
Asprosin blocker trials	Assess the possibility of preventing relapse
Ptprd Research	To determine the effectiveness and safety of the effect on the receptor
Study of pregnancy in humans	Test the mechanism's significance for intergenerational risk
Chromatin research	Find out if it is possible to eliminate molecular memory itself

Research source

Brian C. Kim, Hiba Obeid, Yi Fan Chen, Christopher Kim, Adam Lieberman, Bijoya Basu, Elizabeth S. Silva, Jingzhi Meng, Kyle Starost, Natalia Aladyshkina, Ila Mishra, Seth J. Field, Atul R. Chopra. Adipose TGFβ-asprosin memory promotes obesity relapse and offspring obesity susceptibility. Cell Reports. 2026;45(8):117809. Published in the issue dated August 25, 2026. DOI: 10.1016/j.celrep.2026.117809.