Longevity Briefs: The Immune System ‘Remembers’ Obesity

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Obesity is known to increase the risk of numerous age-related diseases including heart disease, diabetes and even certain cancers. Some of this is explained by obesity’s impact on the immune system, often leading to a state of chronic, low-grade inflammation. This persistent inflammation is thought to be a key driver of many age-related diseases, yet while losing weight undoubtedly improves health significantly, there are unanswered questions about whether the immune system fully recovers.

In this study, researchers investigate the lasting effects of obesity on CD4 T lymphocytes, a type of T cell that coordinates the immune response by activating other immune cells and promoting inflammation. Specifically, they looked at effector memory T cells, which as their name implies, ‘remember’ past infections and allow the immune system to respond more rapidly to subsequent infections. CD4 T cells develop into memory cells following an infection, but previous research had suggested that obesity and high levels of saturated fatty acids could also cause some CD4 T cells to develop into effector T memory cells. These memory cells adopt a particularly pro-inflammatory state, potentially promoting age-related disease and possibly also the regain of weight. Researchers were interested in whether this inflammatory state persisted after obesity was reversed, and if so, for how long.

The discovery:

Researchers first investigated the lasting effects of obesity in a small study of mice. Groups of female mice (around 11 animals per condition) were fed with either a normal chow diet for 14 weeks, a high fat diet for 14 weeks to induce obesity, or a high fat diet for 8 weeks followed by 6 weeks of a normal diet to induce obesity followed by recovery. They then injected mice with white blood cells from other mice in order to induce an immune response. They found that, even though the obesity followed by recovery group had returned to a normal weight, they still had a number of inflammatory effector memory T cells that was comparable to the group that maintained their high-fat diet throughout the 14 weeks.

Inflammatory effector memory T cell counts did start to drop towards normal levels if weight loss was maintained for another 6 weeks, suggesting the effect was reversible, but delayed. 6 weeks is a relatively long time for a mouse, ‘equivalent’ to a few years for a human, but to draw any conclusions from this about the effects of sustained weight loss on effector memory T cells in humans would require heavy assumptions. The researchers therefore conducted similar measurements in two human studies:

• 13 obese patients who were treated with the weight loss drug semaglutide (more commonly known under the brand name ozempic) over a 6 month period
• 27 obese participants who were randomly assigned to either a control group or a 10-week exercise program

They found that in neither case did the intervention significantly alter the effector memory T cell counts, despite the interventions being effective in other ways (though the exercise intervention did not result in a statistically significant BMI reduction). This suggests that in humans, interventions aimed at reversing obesity and the metabolic changes associated with it do not reverse the effect on effector memory T cells, at least in the short term.

In order to understand what was going on at the cellular level, researchers isolated effector T cells from the mice in the initial experiment and looked at DNA methylation. Methylation is the addition of molecular ‘tags’ called methyl groups to the DNA molecule in order to influence gene expression, and is one of the ways in which cells control which genes are ‘switched on’ and to what extent. They found that cells from high fat diet mice and recovered obese mice had similar methylation patterns – in other words, the activity of certain genes had become ‘stuck’ at the levels they were when the mice were obese. One overactive gene in particular – Stk26 – caught the researchers’ eyes.

Stk26 is involved in autophagy – the removal of ‘junk’ from inside the cell. Researchers genetically engineered mice lacking Stk26 and found that these mice did not develop an inflammatory effector memory T cell population when fed a high fat diet, suggesting that increased activity of this gene was playing a critical role in the expansion of these harmful immune cells. Finally, they showed that palmitate, a saturated fatty acid that is abundant in the western-style diet, was able to activate Stk26 in isolated human CD4 T cells.

The implications:

This research suggests that our immune cells may ‘remember’ obesity via changes in DNA methylation, resulting in a population of more inflammatory immune cells .This could potentially contribute to increased risk of age-related disease long after someone is able to regain a normal weight.

This is not the first time that the immune system has been shown to ‘remember’ metabolic conditions – there is research showing that some immune cells become more inflammatory in response to high blood sugar, and remain so even if blood sugar is brought back under control. This may explain why diabetes medication doesn’t reduce risk of cardiovascular diseases (which are driven in part by inflammation) nearly as much as might be expected.

Due to the relatively short duration of the human trials examined in this study, we don’t know how long it takes for effector memory T cell populations to return to normal after weight loss, so this is something for future studies to investigate. It is also possible that some forms of weight loss, like calorie restriction or more intensive/longer exercise interventions, might accelerate the recovery.