New research suggests obesity may leave a long-lasting “memory” on the immune system, even years after weight loss.
Researchers have found that obesity may leave a lasting biological “memory” in the immune system, potentially increasing the risk of obesity-related diseases years after a person loses weight. The findings come from a decade-long study published in EMBO Reports.
The European study was led by Professor Claudio Mauro from the University of Birmingham and supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Birmingham. The team discovered that helper T cells, also known as CD4+ lymphocytes, can retain long-term changes linked to obesity.
Scientists found that a process called DNA methylation adds molecular markers to the DNA of these immune cells. These changes may remain for 5 to 10 years after successful weight loss. Researchers say this lingering “memory” could disrupt important immune system functions, including waste removal and regulation of immune aging.
The research team believes this may help explain why some people remain vulnerable to obesity-related conditions even after reaching a healthy weight.
Long-Term Health Risks After Weight Loss
To better understand obesity’s effects on the immune system, researchers analyzed immune cells from four groups of participants. The study involved:
- Blood samples from people living with obesity who received weight loss injections
- Blood samples from patients with Alstrom Syndrome, a rare genetic disorder linked to early-onset childhood obesity, along with healthy matched participants
- Blood and fat tissue samples from participants in a 10-week exercise program
- Blood and fat tissue samples from people with either obesity or normal weight who had osteoarthritis and underwent hip or knee replacement surgery
Mouse Models and Immune Dysregulation Research
The researchers also examined cells from mice fed a high-fat diet, along with blood samples from healthy human volunteers. These models helped scientists investigate the cellular mechanisms behind immune system dysfunction linked to obesity.
Professor Claudio Mauro, from the Department of Inflammation and Ageing at the University of Birmingham and co-lead author of the study, said, “The findings suggest that short-term weight loss may not immediately reduce the risk of some disease conditions associated with obesity, including type 2 diabetes and some cancers.
“Instead, ongoing weight management following loss will see the ‘obesity memory’ slowly fade. This may take several years of sustained weight loss maintenance, likely 5-10 years, though this requires further study, to fully reverse the effects of obesity on T cells.
“Additionally, our study suggests potential therapeutic opportunities to expedite this process, such as repurposing drugs like SGLT2 inhibitors, which have shown promise in reducing inflammation and promoting immune-mediated clearance of senescent cells in obesity.”
DNA Tagging Pathways and Potential Treatments
The researchers identified two major pathways through which this DNA tagging affects helper T cells.
According to the study, obesity-related immune memory appears to interfere with autophagy (where cells break down and remove waste) and immune senescence (the aging of the immune system). The team hopes these findings will lead to targeted treatments that can restore normal immune function disrupted by DNA methylation. Such therapies could eventually work alongside current weight loss treatments to lower the risk of metabolic diseases and cancer linked to obesity.
Dr. Belinda Nedjai from the Wolfson Institute of Population Health at Queen Mary University London and senior author of the study said, “Our findings show that obesity is associated with durable epigenetic modifications that influence immune cell behavior. This suggests that the immune system retains a molecular record of past metabolic exposures, which may have implications for long-term disease risk and recovery.”
Professor Andy Hogan from the Kathleen Lonsdale Institute for Human Health Research at Maynooth University, Ireland, said, “We know obesity is a chronic, progressive, and relapsing disease, and our findings provide further understanding of exactly what are the molecular mechanisms potentially driving the risk of relapsing and highlight the challenges facing people living with obesity to successfully manage their weight.”
Reference: “DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation” by Jennifer Niven, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Fearon C Cassidy, Ainhoa Arana Echarri, Sadaf Ali, Efthymios Ladoukakis, Sofia Vidali, Chiara Macchi, Sayeda S Amir, Ronan Bergin, Sophie Davies, Oliver J Perkin, Joanne Smith, Danilo Cucchi, Helen Heneghan, Susanne Wijesinghe, Benjamin J Jenkins, Shanat Baig, Christopher Mahony, Chiamaka Chidomere, Sovan Sarkar, Anna Nicolaou, Jorge Caamaño, Adam Croft, Edward Davies, Dylan Thompson, Donal O’Shea, Simon W Jones, Niharika A Duggal, Massimiliano Ruscica, Maria Makarova, Nicholas Jones, Gabriela Da Silva Xavier, Tarekegn Geberhiwot, James E Turner, Andrew E Hogan, Belinda Nedjai and Claudio Mauro, 27 April 2026, EMBO Reports.
DOI: 10.1038/s44319-026-00765-w
The study was delivered through the NIHR Biomedical Research Centre: Birmingham, which supports research focused on improving outcomes for people with multiple long‑term conditions.
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