In the course of research aimed at finding solutions to the global obesity crisis, scientists have discovered that once a person is obese, it becomes very difficult to find effective, long-term weight-loss methods.
However, the exact reason for this remains unclear, though it appears that obesity leaves a lasting imprint on the body—one that persists even after weight loss. A study published earlier this year revealed one mechanism by which our immune cells retain “memories” of obesity.
A new study published in the journal Science Translational Medicine describes a distinct effect of obesity on another group of immune cells located directly within fat tissue; this effect appears to cause irreversible biological changes that directly hinder fat loss.
Researchers from various institutions in Japan analyzed adipose tissue macrophages (ATMs) in mice. These ATMs are the most abundant immune cells in fat tissue, responsible for regulating fat levels and inflammation, fighting infections, and clearing away dead or damaged cells—a process known as efferocytosis.
During experiments involving mice bred to gain and then lose weight, the research team discovered irreversible changes in the animals’ ATMs linked to mRNA splicing—an editing process that controls how genetic instructions are assembled to create proteins.
“These results suggest that the alternative splicing landscape can persist in macrophages as a ‘memory of obesity,’ shaping their phenotypic characteristics,” the researchers write.
The study’s findings involve considerable biological terminology, but the core concept is easy to grasp once the meaning of the letters and numbers is understood. Initially, researchers observed that mice losing the least amount of weight had lower levels of the CWC22 protein in the nuclei of ATM cells.
Further experiments revealed that obesity-induced stress in mice reduced CWC22 levels, impairing the protein’s normal function as a key splicing regulator. Moreover, more than half of the genes in ATM cells remained altered even after the mice began to lose weight.
“Multi-omic and gene-targeting approaches showed that 51.9% of genes with obesity-induced splicing alterations in ATMs remained changed after weight loss, identifying persistent splicing changes as a key component of obesity memory—with a quarter of these changes being CWC22-dependent,” the researchers write.
Thus, changes resulting from reduced CWC22 levels are a crucial part of the “memory” of obesity within these cells. The researchers also determined that the defective splicing affected the Scarb1 gene, which in turn reduced the efficiency of efferocytosis—the waste-clearance system mentioned earlier.
The researchers found that an increase in dead and dying cells led to lower levels of inosine. This molecule helps stimulate lipolysis—the breakdown of stored fat—bringing us back to the issue of weight loss.
Delving into such a remarkable level of cellular detail makes the study somewhat complex to grasp, but it means we have a much better understanding of what is happening and how it might eventually be treated. “These results show that aberrant alternative splicing in macrophages underlies resistance to weight loss following obesity and suggest that splicing-targeted therapies could counteract the ‘memory’ of obesity,” the researchers write.
Effective treatments are still a long way off, and this study was conducted primarily on mice (though some findings were validated in human cells). Nevertheless, it adds important information to what we already know about cells that “remember” obesity.
It is becoming clear that these “memories” take different forms across various cell types and create barriers to recovering from obesity—and the more scientists learn about these barriers, the closer they get to finding ways to overcome them.
“Obesity represents a major global health crisis, characterized by rapidly rising prevalence and associated with reduced life expectancy and a significant socioeconomic burden,” the researchers write. “Effective treatments for obesity include pharmacological therapy, bariatric surgery, and lifestyle changes; however, sustained weight loss remains difficult to achieve, which highlights the need for additional therapeutic strategies.”
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