Obesity may leave a long-lasting biological imprint on the immune system, keeping some health risks elevated years after a person loses weight. A 10-year study published in EMBO Reports indicates that people who previously lived with obesity can retain a molecular memory of that state in key immune cells.
Researchers led by Professor Claudio Mauro at the University of Birmingham found that helper T cells, also known as CD4+ lymphocytes, can carry lingering signs of past obesity. These changes persisted even after participants achieved significant weight loss and moved into a healthier body mass range.
Persistent DNA changes in immune cells
The team focused on DNA methylation, a process in which chemical markers attach to DNA and influence gene activity without changing the underlying genetic code. Their analysis suggests that obesity-related methylation patterns in helper T cells may persist for 5–10 years after weight reduction.
This enduring molecular memory could disrupt normal immune functions, including how cells clear waste and how the immune system ages. Researchers believe these effects may partly explain why people who lose weight can continue to face elevated risks of type 2 diabetes, cardiovascular disease and some cancers.
To build a detailed picture, scientists studied immune cells from several distinct groups. These included people with obesity receiving weight loss injections, patients with Alström syndrome who develop obesity during childhood, and matched healthy controls.
How the study was conducted
The investigation also examined blood and fat tissue from participants who completed a 10-week exercise program. In addition, samples were collected from people with normal weight or obesity undergoing hip or knee replacement surgery because of osteoarthritis.
To investigate the underlying mechanisms more closely, the team used mouse models fed a high-fat diet as well as blood from healthy human volunteers. These experiments helped clarify how excess body fat can drive immune dysregulation and long-term cellular changes.
According to Professor Mauro, short-term weight loss may not immediately erase disease risks associated with obesity. Instead, he says maintaining weight loss over many years is likely necessary for the obesity memory in T cells to gradually fade and for immune function to normalize.
Potential new treatment strategies
The study identified two key pathways influenced by these durable DNA tags: autophagy and immune senescence. Autophagy is the process through which cells break down and recycle their own components, while immune senescence refers to the aging and functional decline of immune cells.
Disruption of these pathways may impair the immune system’s ability to remove damaged cells and respond effectively to metabolic stress. Over time, this could contribute to chronic inflammation and increased susceptibility to age-related diseases.
The authors suggest that certain existing medications might help accelerate the reversal of obesity’s immune imprint. They highlight SGLT2 inhibitors, drugs used to treat type 2 diabetes, which have shown promise in reducing inflammation and promoting the clearance of senescent cells.
Dr Belinda Nedjai of Queen Mary University of London said the findings show that obesity is associated with durable epigenetic modifications that shape immune behavior. She noted that the immune system appears to retain a molecular record of previous metabolic exposures, with potential implications for long-term disease risk.
Professor Andy Hogan from Maynooth University added that the results reinforce the view of obesity as a chronic, relapsing condition rather than a simple lifestyle problem. He said understanding these molecular mechanisms highlights the challenges many people face when trying to maintain weight loss over time.
The work was conducted through the NIHR Biomedical Research Centre: Birmingham, which focuses on improving outcomes for people living with multiple long-term health conditions. The authors say further research is needed to determine how durable these epigenetic changes are and which therapies can most effectively reverse them.
