Obesity Leaves a Lasting Imprint on the Immune System, Study Finds

Key Takeaways: 

• Immune cells in people living with obesity can retain a long-term “memory” of excess weight through epigenetic changes
  
• This “obesity memory” may persist for 5–10 years after weight loss and could prolong disease risk
  
• Sustained weight management may gradually reverse these effects, with potential for targeted therapies to accelerate the process
  
  
  

A long-term immune memory of obesity

People living with obesity may carry a lasting biological imprint of excess weight within their immune system, even after successful weight loss. A 10-year study published in EMBO Reports suggests that key immune cells retain a “memory” of obesity, potentially extending the risk of related health conditions for years.

The research, led by Professor Claudio Mauro at the University of Birmingham and supported by the National Institute for Health and Care Research Biomedical Research Centre in Birmingham, focused on helper T cells, also known as CD4+ lymphocytes. These cells play a central role in coordinating immune responses.

The findings indicate that these immune cells undergo lasting changes that continue to influence how the body regulates inflammation and maintains immune balance long after weight has been reduced.

DNA methylation and the “tagging” process

At the centre of this phenomenon is DNA methylation, a biological process in which chemical markers attach to DNA and alter gene activity without changing the underlying genetic code.

In people living with obesity, this “tagging” process appears to leave a durable imprint on helper T cells. These markers can persist for an extended period, with the study suggesting a timeframe of approximately 5–10 years after weight loss.

This sustained epigenetic modification may disrupt normal immune functions, including the removal of cellular waste and the regulation of immune ageing.

As a result, even individuals who return to a clinically healthy weight may continue to experience altered immune function for several years.

Implications for long-term disease risk

The persistence of this immune “memory” may help explain why the risk of certain conditions associated with obesity does not immediately resolve following weight loss.

Professor Claudio Mauro, co-lead author of the study, explained:
“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.”

He added:
“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.”

The study highlights that long-term weight maintenance, rather than short-term weight loss alone, may be critical for reducing risk over time.

Study design and participant groups

To build a comprehensive understanding of how obesity affects immune cells, researchers analysed samples from multiple human cohorts and experimental models.

These included:

• Blood samples from people living with obesity who received weight loss injections
• Individuals with Alström Syndrome, a rare genetic condition characterised by early-onset childhood obesity, alongside matched healthy controls
• Participants undergoing a 10-week exercise intervention, with blood and fat tissue collected
• People with either a healthy weight or obesity undergoing hip or knee replacement surgery due to osteoarthritis

In addition, the team examined:

• Mouse models fed a high-fat diet
• Blood samples from healthy human volunteers

These diverse data sources enabled researchers to investigate both real-world and mechanistic aspects of immune dysregulation in obesity.

Disrupted cellular processes: autophagy and immune ageing

The study identified two key biological pathways affected by obesity-related DNA tagging:

Autophagy

Autophagy is a cellular “clean-up” process in which cells break down and recycle damaged components. The obesity-related epigenetic changes appear to impair this process, potentially leading to an accumulation of cellular waste.

Immune senescence

Immune senescence refers to the ageing of the immune system. The research suggests that obesity-associated changes may accelerate or dysregulate this process, altering how immune cells respond over time.

Together, these disruptions may contribute to prolonged inflammation and impaired immune function.

Potential for targeted therapies

Beyond identifying the problem, the research also points towards potential therapeutic strategies.

Professor Mauro noted:
“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.”

Such approaches could complement existing weight loss interventions by addressing the underlying immune alterations that persist after weight reduction.

A molecular record of metabolic history

Dr Belinda Nedjai, senior author from the Wolfson Institute of Population Health at Queen Mary University London, emphasised the broader significance of the findings:
“Our findings show that obesity is associated with durable epigenetic modifications that influence immune cell behaviour. 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.”

This concept of a “molecular record” reinforces the idea that the body’s response to obesity is not easily reversed, even when weight is reduced.

Understanding obesity as a chronic disease

Professor Andy Hogan of Maynooth University highlighted how these findings align with the understanding of obesity as a chronic condition:
“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 research underscores the biological complexity of obesity and the challenges individuals face in achieving and maintaining long-term health improvements.

Looking ahead

Delivered through the NIHR Biomedical Research Centre in Birmingham, this study contributes to a growing body of evidence that obesity leaves lasting effects on the body at a molecular level.

Future research will aim to refine understanding of how these epigenetic changes can be reversed and how targeted treatments might accelerate recovery of normal immune function.

In the meantime, the findings highlight the importance of sustained weight management and long-term support for people living with obesity, rather than a sole focus on short-term weight loss.

CCH insights:

This study provides further support for the characterisation of obesity as a chronic relapsing disease. Clinically significant weight loss is just the first step in obesity treatment – the challenge is to then maintain the weight loss so that health improvements are sustained, despite the biological memory of obesity promoting weight regain. Whether this memory reduces over time will have major implications for long-term obesity care in the future.

Source: University of Birmingham