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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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

摘要

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.