DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of "obesity memory", which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.

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Publication Details

Journal
EMBO Reports
Published
2026-04-27
DOI
https://doi.org/10.1038/s44319-026-00765-w
Primary Topic
Immune responses and vaccinations
Type
article
Field-Weighted Citation Impact
0.00

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article

DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Belinda Nedjai, Maria Makarova, Anna Nicolaou, Oliver J. Perkin et al.
EMBO Reports
Immune responses and vaccinations
article

DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Belinda Nedjai, Maria Makarova, Anna Nicolaou, Oliver J. Perkin, James Turner, Féaron C. Cassidy, Claudio Mauro, Shanat Baig, Benjamin Jenkins, Ronan Bergin, Dylan Thompson, Ainhoa Arana Echarri, E. Davies, Michelangelo Certo, Sovan Sarkar, Christopher B. Mahony, Chiara Macchi, Danilo Cucchi, Jorge Caamaño, Chiamaka Chidomere, Nicholas Jones, Jennifer Niven, Andrew E. Hogan, Susanne N. Wijesinghe, Simon W. Jones, Sophie Davies, S. Amir, Sadaf Ali, Niharika Arora Duggal, Salih Kucuk, Efthymios Ladoukakis, Gabriela Xavier, Atrayee Gope, Joanne Smith, Sofia Vidali, M Ruscica, Helen Heneghan, Tarekegn Geberhiwot, Adam Croft, Donal O’Shea
article en

Abstract

Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of "obesity memory", which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.

EMBO Reports
University Hospitals Birmingham NHS Foundation Trust (GB), National University of Ireland, Maynooth (IE), Queen Mary University of London (GB), University of Milan (IT), Manchester Academic Health Science Centre (GB), Royal Orthopaedic Hospital (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), University College Birmingham (GB), Swansea University (GB), Ospedale Maggiore (IT), Charles River Laboratories (United Kingdom) (GB), Birmingham Women's Hospital (GB), St. Vincent's University Hospital (IE), Adc Therapeutics (Switzerland) (CH), Reaction Biology (Germany) (DE), William Harvey Research Institute (GB), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Bath (GB), University of Birmingham (GB)
LifeArc, Action Medical Research, British Heart Foundation, Baqiyatallah University of Medical Sciences, Versus Arthritis, Medical Research Council, HORIZON EUROPE Marie Sklodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 13%
Immune responses and vaccinations
DOIOpen Access PDFOpenAlex
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