Immune Cells May Keep a Biological Memory of Obesity
Key Takeaways:
- Mice lacking a protein called CWC22 in their fat tissue immune cells struggled to lose weight on a reduced-fat diet.
- Over half of the obesity-related genetic changes in these cells persisted after weight loss, suggesting a biological “memory” of obesity.
- Correcting one of those changes restored normal cell function and helped the mice shed fat again.
Why weight loss can become harder after obesity
According to the World Health Organization, one in eight people worldwide lives with obesity. Yet despite the volume of health education programmes, books, articles and treatments available, many people continue to find weight loss extremely difficult once obesity has developed. Precisely why the body resists losing weight, and why lost weight is so often regained, remains a complex puzzle for researchers.
A new study published in the journal Science Translational Medicine may offer part of the answer. The research points to changes in a particular type of immune cell known as an adipose tissue macrophage (ATM). In mice, these changes appeared to make weight loss harder, because the cells seem to carry a biological “memory” of obesity that outlasts the obesity itself.
What the researchers did
Researchers from several institutions across Japan set out to study ATMs directly. These immune cells help regulate fat tissue health in a number of ways, one of the most important being the safe removal of dying cells from the tissue.
The team fed laboratory mice a high-fat diet for 12 weeks until the animals developed obesity, then switched them to a low-fat diet for a further six weeks. When they compared the animals, they noticed a pattern: the mice that lost the least weight after the dietary switch had lower levels of a protein called CWC22 in the nucleus of their ATM cells. This suggested that CWC22 might play a role in helping the body shed weight.
To test that idea, the researchers genetically modified a group of mice so that they lacked the CWC22 gene in a group of immune cells that includes macrophages. Under normal circumstances, CWC22 helps cells splice messenger RNA, the editing process that RNA undergoes before it is used as a template to make proteins.
A clean-up failure in fat tissue
When the modified mice were placed on a weight-loss diet, they struggled to shed fat. Their ATMs could not clear away dead cells effectively, and as a result dead cells accumulated in the fat tissue.
Closer analysis of these immune cells revealed the mechanism. The absence of the Cwc22 gene caused a splicing error involving a gene called Scarb1. Because of that error, the macrophages destroyed their own clean-up receptors before those receptors could reach the cell surface, leaving the cells without the tools they needed to do their job.
The knock-on effect involved a chemical messenger. Because the macrophages were less able to clear dead cells, they released less inosine. Inosine normally acts as a signal instructing fat cells to break down their stored fat, so with less of it available, fat breakdown was impaired.
A memory that persists after weight loss
Perhaps the most striking finding concerned how long these changes lasted. The research team found that 51.9% of the genes showing obesity-induced RNA splicing changes in these immune cells remained altered even after the animals had lost weight.
In other words, the immune cells retained a biological record of the period of obesity, including alterations that continued to impair their normal clean-up duties long after the diet had changed.
“These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss,” commented the study authors in their paper.
Rewriting the memory
Encouragingly, at least one component of that memory appears to be reversible. When the scientists corrected the Scarb1 splicing error using a synthetic genetic patch, the clean-up receptors were restored. This in turn increased the amount of inosine available and helped the mice to lose fat once again.
“Our study suggests that specific alternative splicing events can shape macrophage phenotypes under defined environmental conditions.”
What this could mean for people living with obesity
The findings may eventually help inform treatments for people who struggle to lose weight after developing obesity. When the team analysed human tissue samples, they found abundant CWC22 in the nuclei of immune cells taken from people who were lean, but reduced levels in samples from people living with obesity. That parallel between the mouse and human findings is what makes the work potentially translatable.
It is worth keeping the limitations in view. The functional experiments were carried out in mice, and the human element of the study was limited to tissue analysis rather than any test of treatment. No synthetic genetic patch has been trialled in people, and there is a considerable distance between correcting a splicing error in a mouse model and offering a therapy in clinical practice.
Even so, the study adds to a growing body of evidence that weight regain is not simply a matter of behaviour or willpower. Biological adaptations in fat tissue, appetite regulation and now immune cell function all appear to work against sustained weight loss. Clinicians who want to explore these mechanisms and their practical implications in more depth may find it useful to look at structured CPD, such as the College of Contemporary Health’s Obesity Essentials short course, which covers the biological, clinical and behavioural drivers of obesity and weight management.
For people living with obesity, findings like these carry a useful message: the difficulty of maintaining weight loss has measurable biological underpinnings, and understanding them may in time lead to better-targeted support.
CCH insight
Understanding why the body resists weight loss is central to supporting people living with obesity well. Our Obesity Essentials CPD short course explores the physiology, clinical management and behavioural dimensions of obesity, giving healthcare professionals a grounded, evidence-informed basis for the conversations they have every day.
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