[Measuring the belly. Photo Credit to Pixabay]

On April 27th, 2025, scientists announced in the international journal, EMBO Reports, that obesity leaves epigenetic marks on DNA in immune cells which cause chronic conditions even after weight loss.

Even after an individual who underwent obesity returned to their regular, healthy weight, it is still common for them to face relapsed inflammation and immune dysfunction, alongside risks of other certain diseases due to fat cells retaining memory of obesity.

However, recently a European joint research team, led by Professor Claudio Mauro from the University of Birmingham in UK and supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre, discovered a more precise mechanism behind this phenomenon.

The team analyzed blood and adipose tissues from four main different cohorts, which included individuals with obesity who either exercised four times a week for 10 weeks or received injections of semaglutide for weight loss.

Additionally, a control group consisted of healthy adults, and samples were also collected from patients with Alström syndrome – a rare genetic disorder correlated to  childhood obesity, as well as from normal weight and obese patients who underwent total hip or knee replacement for osteoarthritis, a chronic joint disease.

Through a decade-long research effort, scientists were able to determine that immune cells had also carried a persistent memory of obesity by connecting this to a mechanism – DNA methylation.

Epigenetic marks are chemical tags that do not physically change the DNA sequence itself, but rather perform similarly as a switch, controlling only the gene expression.

However, in a state of obesity, epigenetic marks are left on the DNA within helper T cells, which belong to the lymphatic immune system and are also known as CD4+ lymphocytes, continues to promote dysregulated, pro-inflammatory conditions –  forcing cells to contain long-term memory of obesity.

This had driven the T cells towards an aggressive and pro-inflammatory effector memory phenotype, as well as saturated fatty acids.

As a result, rather than altering the DNA sequence itself, the marks block certain genes from being read, also controlling the degree of gene expression and molecular memory of prior metabolic state.

Additionally, scientists also found out that the ‘obesity memory’ remaining in helper T cells disrupts immune functions when it comes to two pathways.

These included autophagy, a cellular clean up which is the process where cells break down and remove their own waste, as well as immune aging, also known as immune senescence.

As cleaning functions deteriorate and immune aging is accelerated, damaged cell and protein debris increases while the prematurely declining immune system weakens defense against infections and maintains homeostasis.

To add on, due to dysfunction of immune cells and preserved memory, it could elevate risks of obesity-related illness – having no correlation with returning to a normal weight.

The ongoing immune memory may help explain why relapse and long-term complications are common in obesity.

In order to further support this, scientists analyzed mice which were fed high-fat diets and blood from adult volunteers.

Resultingly, the effect lasted for weeks in mice, while its existence and duration in humans are still to be determined.

The most striking finding of this study was the durability of these marks, which could possibly remain for five to ten years after returning to a normal weight.

This underscores the enduring, detrimental impacts of obesity, possibly indicating how it is not simply a reversible metabolic state, but withholds the capability of inducing long-term immune reprogramming.

Professor Mauro, the senior author of the study, stated as well, "Short-term weight loss alone does not immediately lower the risk of obesity-related diseases such as type 2 diabetes or some cancers. It appears that 5 to 10 years of sustained weight management are needed for the 'obesity memory' to gradually fade and to fully reverse the effects of obesity on T cells."

Fortunately, the findings carried direct implications for how obesity could be managed clinically, as well as deepen understanding on how short-term interventions may not be sufficient.

The research team plans to develop therapies aiming to restore normal immune functions suppressed by these DNA marks. 

This will be done alongside supportive weight loss treatments, such as SGLT2 inhibitors  – a type 2 diabetes treatment known to lower the risk of obesity-related diseases by efficiently reducing inflammation and aging cells in obese patients.

These findings emphasize that weight loss is only a small fraction of obesity treatment.

Instead, obesity operates as a “chronic immuno-metabolic disease” tied directly to the immune system, explaining why individuals often remain vulnerable to obesity-related conditions even after losing weight.

Just as Andy Hogan, PhD,of Maynooth University emphasized how “obesity is a chronic progressive and relapsing disease,” the study helps explain the biological basis of that persistence.