A decade-long study, detailed in the journal EMBO Reports, suggests that individuals who have been obese “imprint” a memory of their excess weight onto a critical part of the immune system, leading to a persistent susceptibility to obesity-related ailments years after weight loss is achieved.
A European research team, headed by Professor Claudio Mauro from the University of Birmingham, discovered that immune cells known as T-helper cells (or CD4+ lymphocytes) retain a long-lasting recollection of obesity.
Through a process involving DNA methylation, tags or markers become attached to the DNA of these immune cells. This “labeling” is likely retained for five to ten years subsequent to a person successfully shedding weight. The resulting “obesity memory” within T-helper cells may impair certain normal immune functions, including waste removal and the governance of immune system aging.
The investigative team posits that this mechanism could mean that individuals who lose weight remain at risk for developing obesity-associated conditions long after reaching a healthy weight.
To gain a comprehensive view of obesity’s impact, researchers obtained immune cells from four distinct patient cohorts. The study encompassed:
Collecting blood from obese patients undergoing weight-loss injections.
Gathering blood from individuals with Alström syndrome, a rare genetic disorder characterized by obesity onset in childhood, alongside healthy, matched control pairs.
Obtaining blood and fat tissue samples from a group participating in a 10-week physical exercise regimen.
Securing blood and fat tissue samples from both normal-weight and obese individuals suffering from osteoarthritis who underwent hip or knee replacement surgery.
The research also incorporated analyses of cells from mice maintained on a high-fat diet, and blood specimens from healthy human volunteers. These models were employed to investigate the intracellular mechanisms underpinning impaired immune regulation linked to obesity.
“The findings imply that short-term weight loss might not immediately mitigate the risk for certain obesity-related diseases, such as type 2 diabetes and some cancers,” stated study co-author Professor Claudio Mauro, from the University of Birmingham’s Department of Immunology and Ageing. “Instead, sustained weight management post-loss will be necessary for the gradual erasure of this ‘obesity memory.’ This could require several years of consistent weight maintenance, potentially five to ten, although further study is warranted to fully reverse the effects of obesity on T-cells.”
“Furthermore, our research points towards promising therapeutic avenues for hastening this reversal, such as repurposing medications like SGLT2 inhibitors, which have proven effective in reducing inflammation and promoting immune-mediated clearance of senescent cells in obesity,” he added.
The research group pinpointed two specific pathways through which this labeling affects T-helper cells.
It is believed that the obesity memory influences autophagy (the cellular process where cells ingest their own components to clear waste) and immunosenescence (the aging process of the immune system). The team intends to leverage this data to seek targeted treatments that can restore normal immune function suppressed by DNA methylation.
Resulting potential therapies could be used alongside existing weight reduction strategies to lessen the probability of developing conditions like metabolic disorders and cancer, which obesity exacerbates.
“Our results demonstrate that obesity results in persistent epigenetic modifications that alter immune cell behavior. This suggests that the immune system maintains a molecular record of prior metabolic exposures, which holds implications for long-term disease risk and recovery,” commented study co-author Dr. Belinda Nejjai, from Queen Mary University of London’s Barts and The London School of Medicine and Dentistry, Wolfson Institute of Population Health.
“We recognize that obesity is a chronic, progressive, and relapsing condition, and our findings offer deeper insight into the specific molecular mechanisms potentially dictating relapse risk, highlighting the inherent difficulties faced by obese individuals in successfully managing their weight,” concluded Professor Andy Hogan from Maynooth University’s Kathleen Lonsdale Institute for Human Health Research in Ireland.
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