EMBO Rep
Obesity may leave immune memory after weight loss
Clinical takeaway: Weight reduction may improve metabolic health before immune function fully resets, so sustained weight maintenance and immune-targeted therapies may be important after obesity.
Weight loss reduces obesity-related risk, but this study suggests the immune system may not recover as quickly as body weight or metabolic markers. Investigators examined whether helper T cells retain a molecular memory of obesity that could help explain persistent inflammation and disease risk after weight reduction.
In 13 patients treated with semaglutide for weight management, weight and hemoglobin A1c improved after 6 months, but inflammatory effector memory T-cell populations didn't significantly return toward immune homeostasis.
A second cohort included 10 people with Alström syndrome and 10 matched controls; those with the rare early-onset obesity disorder had higher effector memory T-cell populations. In a separate exercise intervention with 27 participants, improved fitness didn't significantly change these T-cell populations in blood or fat tissue.
Mouse and cell analyses pointed to DNA methylation as a possible driver of this immune memory, with autophagy and immune senescence emerging as key pathways. The authors suggest these pathways could eventually become targets to help restore immune homeostasis after weight loss.
“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,” said Claudio Mauro, PhD, professor in the Department of Inflammation and Ageing at the University of Birmingham.
“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,” he continued.
Concluded Mauro, “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.”
Source: Niven J. EMBO Rep. 2026 Apr 27. DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation