Obesity Memory in Immune Cells May Block Weight Loss

Obesity memory in fat-tissue immune cells

As researchers seek solutions to the worldwide obesity crisis, studies have shown that, once a person develops obesity, finding weight-loss approaches that remain effective over the long term can be exceptionally challenging.

Precisely why this happens is less certain. However, obesity appears to leave a lasting mark on the body, persisting even when weight loss begins. A study released earlier this year identified one mechanism through which immune cells retain ‘memories’ of obesity.

A new study, published in Science Translational Medicine, now outlines another effect of obesity on a different group of immune cells found within fat tissue. It appears to produce lasting biological alterations that directly hinder fat loss.

Researchers from several institutions in Japan examined adipose tissue macrophages (ATMs) in mice. ATMs are the most plentiful immune cells in fat tissue. They regulate fat levels and inflammation, combat infection, and remove dead or damaged cells through a process known as efferocytosis, which is discussed further below.

In experiments involving mice bred to gain weight and subsequently lose it, the team detected lasting changes in the animals’ ATM cells connected to mRNA splicing. This is the editing mechanism that determines how genetic instructions are assembled to produce proteins.

"These findings suggest that the alternative splicing landscape can be retained in macrophages as an 'obesity memory', shaping their phenotypic outcomes," write the researchers in their published paper.

CWC22 and persistent mRNA splicing changes

The findings contain considerable biological terminology, but their central point is easier to understand once the relevant letters and numbers are explained. The researchers first observed that the mice which lost the smallest amount of weight had lower levels of the protein CWC22 in the nuclei of their ATM cells.

Additional experiments showed that the stress produced by obesity in mice lowered CWC22 levels, stopping the protein from carrying out its usual role as an important splicing editor. More than half of the genes in ATM cells also stayed altered after the mice had begun to lose weight.

"Multiomics and gene-targeting approaches revealed that 51.9 percent of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22," write the researchers.

This means the changes resulting from reduced CWC22 form an important part of obesity ‘memory’ in these cells. The team then found that the incorrect splicing affected a gene named Scarb1. This, in turn, made efferocytosis - the cellular waste-removal process mentioned earlier - less effective.

How obesity memory may obstruct fat loss

The scientists found that a larger accumulation of dead and dying cells reduced inosine levels. Inosine is a molecule that helps trigger lipolysis, the process through which stored fat is broken down, bringing the findings back to the challenge of weight loss.

Examining the process in such remarkable cellular detail makes the study more difficult to interpret, but it also provides a clearer picture of what is happening and how it could eventually be addressed.

"These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory," write the researchers.

Potential treatments remain far in the future, and the research focused primarily on mice, although certain results were confirmed in human cells. Nevertheless, it adds important information to existing knowledge about cells that retain obesity memories.

It is increasingly apparent that these ‘memories’ occur in distinct forms across different cell types. They create obstacles to recovery from obesity, and greater scientific understanding of those obstacles could bring researchers nearer to overcoming them.

"Obesity constitutes a profound global health crisis, marked by a rapid increase in its prevalence, and is linked to diminished life expectancy and substantial socioeconomic burdens," write the researchers.

"Effective treatments for obesity include pharmacological therapies and bariatric surgery, in addition to lifestyle modification; however, sustained weight loss remains difficult to achieve, highlighting the need for additional therapeutic strategies."

The research was published in Science Translational Medicine.

This article was fact-checked and edited by Fiona MacDonald. While we take pride in our process, we are only human. If you notice an error, please let us know.