Losing weight is one challenge. Keeping it off can be another.
Scientists have long known that the body often responds to weight loss in ways that make regain more likely, including stronger hunger signals and changes in how much energy the body uses. New research in mice suggests fat tissue itself may also hold onto a biological effect of prior obesity, even after weight comes down.
In the study, published in Cell Reports, researchers found that mice that had previously had obesity continued producing higher levels of asprosin, a hormone that can increase appetite, after they lost weight. When the researchers blocked that signal, the animals were less likely to regain excess weight.
The finding is intriguing, but it is still early. Most of the experiments were done in mice and laboratory-grown cells, and the researchers say they do not yet know how much this process contributes to weight regain in people.
The study also comes with financial disclosures that are important to note. Senior author Atul Chopra has patents related to asprosin and ownership or leadership interests in companies connected with related research and intellectual property. Another author reported an ownership and leadership interest in one of those companies. Those relationships do not invalidate the findings, but they matter because the researchers see this pathway as a possible target for future obesity treatments.
To understand what might be driving the lingering hunger signal, the researchers focused on changes in fat cells during obesity.
They found that exposure to a signal associated with obesity appeared to leave the cells producing more asprosin even after that initial signal had faded. In the mouse experiments, that higher asprosin level persisted after weight loss.
The researchers describe this as a kind of biological “memory.” That does not mean fat cells literally remember in the way a brain does. Rather, some of the cells remained more active in producing the hormone after the original trigger was gone.
The next question was whether that lingering change actually mattered.
Mice with prior obesity lost either about 10% or about 25% of their body weight. Even after weight loss, their asprosin levels remained elevated. When they were later given a high-fat diet, they regained more weight than mice that had not previously had obesity. They also ate more.
When the researchers interfered with the asprosin signal, the extra weight regain was reduced or prevented in the mouse models. That suggests the hormone may be one piece of the biological pressure pushing weight back up after loss.
But it is unlikely to be the whole story.
The body goes through several changes after weight loss. Hunger hormones can shift, feelings of fullness may change and the body may burn fewer calories than before. The researchers themselves note that the asprosin pathway would likely work alongside those other changes, not replace them as an explanation.
That is one reason the study should not be read as having “solved” weight regain.
The researchers did look at limited human data. In one previously collected dataset, activity of the gene involved in making asprosin did not fall after people lost about 10% of their body weight on a low-calorie diet. That is consistent with the mouse findings, but it does not prove the same process drives weight regain in humans.
The study also did not test people taking GLP-1 medications such as Wegovy or Zepbound.
The authors suggest the findings could eventually help explain why some people regain weight after stopping treatment, but that has not been demonstrated here. The mouse experiments cannot tell us why an individual person gains weight back after stopping a GLP-1 drug.
The researchers also explored whether the same biological signal could affect obesity risk in offspring.
In mouse experiments, offspring exposed to higher levels of the signal before birth later showed higher asprosin levels and gained more weight when fed a high-fat diet. The effect was reduced when researchers blocked the pathway.
That finding is also preliminary and should not be applied directly to people. Childhood obesity is influenced by many factors, including genetics, food environment, family habits, social conditions and other biological influences. The authors acknowledge that their mouse experiments cannot capture the complexity of human pregnancy or childhood obesity.
For now, the study offers a possible new piece of a much bigger puzzle.
In mice, prior obesity appeared to leave behind a lasting change that kept an appetite-related signal elevated after weight loss. If future studies confirm that the same thing happens in people, it could help researchers better understand why maintaining weight loss is often so difficult and whether new treatments could help.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, other National Institutes of Health funding, the Harrington Investigatorship, the Harrington Discovery Institute and the Diabetes Action Research and Education Foundation. Senior author Atul Chopra disclosed asprosin-related patents and ownership or leadership interests in Aceragen, Recall Therapeutics and Pathway21, along with related intellectual property. Author Bijoya Basu disclosed an ownership interest and leadership role in Recall Therapeutics. The paper also reported that AI tools were used for language refinement and early versions of two figures, which the authors said they later reviewed and edited.