A study explains the biological resistances that promote the "rebound effect" in obesity.

Obesity has a memory and leaves a deep mark on the body. Although the collective imagination has simplified excess body fat as an individual's lack of willpower , laziness, or inattention to losing weight, science is showing that extremely complex mechanisms exist behind obesity that go beyond individual intentions or determination to challenge the scale. A study published this Wednesday in the journal Nature has described how adipose tissue (body fat) behaves in obesity and after weight-loss surgery; and has discovered that, indeed, when weight is lost, key changes occur at the molecular level that explain the observed health benefits. However, biological resistances also persist, promoting the rebound effect and worsening metabolic dysfunction in the long term.

Specifically, the researchers have revealed that, although weight loss restores some molecular mechanisms altered in obesity —damaged cells are eliminated and harmful fats are metabolized more efficiently—abnormal cellular processes and behaviors persist. Specifically, they noted, some immune system cells remain primed for a possible regain of the lost weight. “This study reinforces the message that weight loss can be very beneficial for health, but it is not perfect. Staying slim is the healthiest state. The research also provides new information for exploring better ways to treat harmful diseases caused by obesity,” summarizes William Scott, a researcher at Imperial College London and author of the study.

This isn't the first time science has shown that the memory of obesity is written in our cells. Less than a year ago, another study also showed, in mouse models and human cells, a molecular mechanism—specifically, epigenetic changes—in fatty tissue that predisposes us to gain weight after losing it. The new study, published in Nature , has found that immune system cells, macrophages, remain activated after weight loss. This means they remain in a favorable position to "trigger possible weight regain and worsen metabolic dysfunction," they explain in the article.

The research, which analyzed more than 170,000 fat tissue cells from 70 people (healthy controls and people with obesity before and after bariatric surgery ), has managed to build a kind of atlas that illustrates how body fat is remodeled when we lose weight, says Scott: “One of the main functions of adipocytes [fatty tissue cells] is to store and release fats when we need them. In obesity, adipocytes become too large and cannot store more fats, causing harmful fats to be deposited in inappropriate places. We discovered that weight loss seems to activate fat recycling in adipocytes. We believe that this recycling reabsorbs harmful fats from other organs, which has beneficial effects on overall and organ health,” the scientist notes in an email response.

After weight loss, the researchers observed a decrease in senescence, a process by which cells stop reproducing, but don't die. Instead, they remain in the tissues, releasing substances that can cause inflammation and damage to neighboring cells. They also saw a reduction in adipocyte hypertrophy: "When adipocytes grow too large and become overstretched, they stop functioning properly and release harmful stress signals. An interesting finding was that weight loss reduces adipocyte hypertrophy and the stress response. When this happens, adipocytes begin to actively recycle harmful fats. These effects, either individually or in combination, appear to be beneficial for health," Scott says.

Deep-rooted changes in cells

Weight loss reverses many of the molecular changes that occur in obesity, but not all, the British scientist warns: “We believe this is because some changes become entrenched in our cells, making them difficult to eliminate. In our study, this resistance appeared to be stronger in immune cells than in adipocytes,” he explains, referring to those macrophages that remain activated. Despite weight loss, these inflammatory immune cells, which infiltrate the fat of obese people, did not fully recover.

Regarding the scientific findings that support an obesity memory embedded in cells, Scott believes that these persistent alterations in the body can have two important consequences for patients: “Epigenetic memory can promote the yo-yo effect and lead to weight regain. But, equally important, it can leave an inflammatory memory in the fat that worsens future health complications after weight regain.”

Daniel Castellano, a researcher with a PhD in the Department of Surgical Specialties, Biochemistry, and Immunology at the University of Malaga and in the Oncobiota Laboratory of the Clinical and Translational Cancer Research Group at IBIMA, was a co-author of that other research, which identified epigenetic changes in adipose tissue that predispose to weight regain. These are "complementary works," he says, referring to this new study, in which he did not participate. "This research gives us an understanding of the cellularity of adipose tissue, and we can see how there is a remodeling of various cell types: there are different cell types that, through what they release or produce, could be affecting other cell subtypes and contributing to what we see in the cell nucleus, which is epigenetics."

Andreaa Ciudin, head of the Comprehensive Obesity Treatment Unit at Vall d'Hebron Hospital in Barcelona and a member of the board of directors of the Spanish Society for the Study of Obesity (Seedo), asserts that Scott's research, in which she also did not participate, confirms that "adipose tissue has memory, and that explains weight regain and weight recovery." "The most important message is that there is biology behind this weight regain after calorie restriction. We need to take the blame off people," she emphasizes.

The most important message is that there's biology behind this weight regain after calorie restriction. We need to take the blame off people.

Andreaa Ciudin, head of the Comprehensive Obesity Treatment Unit at Vall d'Hebron Hospital in Barcelona

Ana Belén Crujeiras, director of the Epigenomics in Endocrinology and Nutrition group at the Santiago de Compostela Health Research Institute (IDIS) and CIBEROBN, also highlights that research such as this "reinforces the need to prevent obesity because, when it develops, an epigenetic and inflammatory memory is established that is very difficult to reverse." The researcher, who is also a member of Seedo, also points out that, in terms of impact on health, "there is evidence that the yo-yo effect is worse because the inflammatory state is exacerbated," and inflammation is, precisely, the "molecular link" that links obesity with the development of other diseases, such as diabetes, cancer, or cardiovascular problems, the scientist adds.

One of the big unknowns that remains to be discovered, Ciudin points out, is whether new obesity treatments, such as Ozempic , "will play a role in preventing this weight regain." It's also unclear, Scott admits, whether the molecular remodeling they've described after bariatric surgery would be similar after other calorie restriction techniques , such as traditional diets or anti-obesity drugs. "We discovered that weight loss causes numerous changes in adipose tissue. For us, the most important question now is which of these changes are most important for health," the scientist agrees.