Obesity leaves a lasting memory in immune cells

The European research team, led by Professor Claudio Mauro at the University of Birmingham and supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Birmingham, found that helper T cells (or CD4+ lymphocytes) can retain signs of past obesity long after body weight has been reduced.

Obesity May Leave Long-Lasting DNA Marks

The researchers focused on a process called DNA methylation, in which chemical tags or markers attach to DNA inside immune cells. Their findings suggest that these changes may persist for 5-10 years following successful weight loss.

This lingering "memory" of obesity in helper T cells could interfere with normal immune functions. Among the processes that may be affected are the removal of cellular waste and the regulation of immune aging. According to the researchers, these lasting changes may help explain why people who lose weight can remain at increased risk for obesity-related diseases even after returning to a normal weight.

To build a detailed picture of how obesity affects the immune system, the researchers analyzed immune cells from four different groups of people. The study included:

• Blood collected from patients who were living with obesity and received weight loss injections,
• Blood collected from patients with a rare genetic disorder called Alstrom Syndrome characterized by early-onset childhood obesity, and healthy matched pairs,
• Blood and fat tissue collected from participants who completed a 10-week exercise intervention
• Blood and fat tissue collected from either normal weight or obesity cohorts with osteoarthritis undergoing total hip or knee replacement surgery.

The team also examined cells from mice models fed on a high-fat diet, along with blood donations from healthy human volunteers. These additional models helped the researchers investigate the cellular mechanisms that contribute to immune dysregulation in obesity.

Why Health Risks May Persist After Weight Loss

Professor Claudio Mauro from the Department of Inflammation and Ageing at the University of Birmingham, who is 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 May Affect Cell Cleanup and Immune Aging

The researchers identified two particular biological pathways that appear to be influenced by these lasting DNA changes in helper T cells.

One is autophagy (where cells eat bits of themselves to clean away the waste), a process cells use to remove damaged or unnecessary material. The other is immune senescence (which is aging of the immune system).

The team plans to use these findings to investigate targeted therapies that could restore normal immune activity when it is disrupted by obesity-related DNA tagging. Such treatments could potentially be used alongside existing weight loss therapies to lower the risk of metabolic diseases, cancer, and other conditions that can be worsened by obesity.

Dr. Belinda Nedjai from the Wolfson Institute of Population Health at Queen Mary University London and senior author of the paper 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."

The study was carried out through the NIHR Biomedical Research Centre: Birmingham, which supports research aimed at improving outcomes for people living with multiple long-term conditions.