A new study has suggested that T cells might retain a pro-inflammatory phenotype long after normal weight is regained following a period of obesity. In mice, the effect lasts for weeks, while its existence and duration in humans are to be determined [1].
The inflammation that stays
Obesity is a chronic, relapsing condition linked to many adverse health outcomes and increased mortality [2]. The difficulties involved in losing weight and not regaining it are well-known, and even if the endeavor is successful, recent research has found that the consequences of obesity might linger long after returning to a normal weight. However, the mechanisms behind these long-term effects are not completely understood. A new study by a European research team suggests that helper T cells remain in the obesity-associated state for a long time, possibly continuing to drive health risks.
Healthy abdominal fat tissue is patrolled by anti-inflammatory immune cells, most notably regulatory T cells (Tregs), which dampen inflammation. In obesity, the immune milieu shifts towards pro-inflammatory cells, which produce chronic low-grade inflammation that drives metabolic disease [3]. Some of the authors of this new study have previously shown that obesity specifically drives CD4+ (helper) T cells toward the especially aggressive and pro-inflammatory effector memory (Tem) phenotype and that saturated fatty acids (SFAs) like palmitate and stearate, which are abundant in high-fat Western diets, can signal directly to CD4+ T cells to drive this bias [4].
Confirmed in mice and (sort of) in humans
To dig deeper, the team started with cohorts of female mice on different diets to model obesity and recovery: chow diet (CD) for 14 weeks, high-fat diet (HFD) for 14 weeks, or HFD for 8 weeks followed by 6 weeks of chow (HFD-RE, “recovery”). Basically, the researchers wanted to see whether getting the mice back on a healthy diet would normalize things. At the end of the experiment, the mice received an antigenic challenge to investigate their T cells’ response.
The HFD-RE mice fully normalized their adipose tissue mass back to chow-fed levels, so by the metric of fat, “recovery” worked. Despite this metabolic recovery, the inflammatory Tem response remained stuck at HFD-like levels in the 14-week recovery group.
Importantly, a male cohort showed comparable HFD-induced Tem expansion, but there was no recovery period. The female-only composition of the main cohorts might have been chosen to maximize the chances of discovery as females have stronger adaptive immune responses, but this is also a genuine gap limiting the results’ generalizability.
When recovery was extended to 12 weeks, the Tem populations did normalize toward CD levels, suggesting that the immune dysregulation is reversible but only with prolonged weight maintenance. Using a mouse-to-human age conversion, the researchers extrapolated this to suggest several years of sustained weight control might be needed in humans, though this is just a hypothesis.
Professor Claudio Mauro from the Department of Inflammation and Aging at the University of Birmingham, a co-lead author of the study, said, “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. Instead, ongoing weight management following loss will see the ‘obesity memory’ slowly fade. This may take several years of sustained weight loss maintenance, likely five to 10 years, though this requires further study, to fully reverse the effects of obesity on T cells.”
To test whether this finding is human-relevant, the authors examined three human cohorts: patients with obesity treated for 6 months with a GLP-1 receptor agonist; people with Alström Syndrome, a rare monogenic obesity-causing disorder; and people who had participated in a 10-week randomized controlled trial of exercise. Neither the semaglutide cohort nor the exercise cohort showed T cell normalization, despite the real weight loss in the former and the metabolic improvements in the latter. This resembles the already familiar delay in getting T cells back to normal, at least in these relatively short timeframes.
Methylation and autophagy
Next, the team performed a DNA methylation analysis on naive and memory T cells from the spleens of the three 14-week mouse groups. They identified 104 genes whose methylation in memory T cells was similarly altered in HFD and HFD-RE compared to CD – i.e., genes where the methylation changes “stuck” through weight loss. Two hypomethylated genes popped out (hypomethylation suggests chromatin derepression, meaning that the gene is more active): Bcl6, a transcription factor known to drive memory T-cell differentiation, and Stk26, an inducer of intracellular junk removal (autophagy).
Inflammatory Tem cells in the HFD-RE group indeed showed sustained autophagy flux, significantly higher than in the CD group. While autophagy is generally associated with lower inflammation, here it possibly indicates increased Tem activity and fitness.
Given their previous results with saturated fatty acids, the researchers wanted to test whether SFAs alone could induce these changes. They treated human CD4+ T cells from healthy donors with palmitate, stearate, or oleate (the unsaturated control). Both palmitate and stearate increased the proportion of Tem cells. Stearate also reduced regulatory T cells. Palmitate specifically upregulated STK26 in activated helper T cells and increased autophagy.
To test causality, the team then put STK26-deficient mice on 8 weeks of CD or HFD. STK26 knockout impaired autophagy and reduced antigen-induced expansion of inflammatory Tem populations on both CD and HFD. The means that autophagy via STK26 is required for the Tem expansion, which is evidence of a causal role.
Apart from using mainly female mice, the study had several more limitations. Most importantly, further studies must be conducted to confirm the effect and its duration in humans. Regarding possible translational implications, Mauro said: “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.”
Literature
[1] Niven, J., Kucuk, S., Gope, A. et al. (2026). DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation. EMBO Rep
[2] Abdelaal, M., le Roux, C. W., & Docherty, N. G. (2017). Morbidity and mortality associated with obesity. Annals of translational medicine, 5(7), 161.
[3] Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., … & Mathis, D. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature medicine, 15(8), 930-939.
[4] Mauro, C., Smith, J., Cucchi, D., Coe, D., Fu, H., Bonacina, F., … & Marelli-Berg, F. M. (2017). Obesity-induced metabolic stress leads to biased effector memory CD4+ T cell differentiation via PI3K p110δ-Akt-mediated signals. Cell metabolism, 25(3), 593-609.
View the article at lifespan.io
