Immune cells may have a biological memory that makes weight loss harder after obesity
According to the World Health Organization, one in eight people lives with obesity. Yet despite numerous health education programs, books, articles and treatments, many individuals still struggle to lose weight once they have developed obesity. Why this is so difficult remains a complex puzzle for scientists.
A recent study published in Science Translational Medicine suggests that obesity may leave a biological "memory" in immune cells, making weight loss more challenging for some individuals. Researchers from multiple Japanese institutions discovered that adipose tissue macrophages (ATMs) - immune cells responsible for regulating fat tissue health - carry this memory in mice.
When these mice were placed on a high-fat diet for 12 weeks and then switched to a low-fat diet, those that lost the least weight had fewer CWC22 proteins in their ATM cells. CWC22 plays a role in helping the body shed weight by assisting in RNA splicing. When scientists genetically modified mice to lack the Cwc22 gene in macrophage cells, the mice struggled to lose fat on the weight-loss diet.
This was due to macrophages failing to effectively clear dead cells, leading to an accumulation of dead cells in fat tissue. This deficiency caused a splicing error in the Scarb1 gene, preventing macrophages from properly disposing of dead cells. Consequently, macrophages released less inosine, a chemical that signals fat cells to break down stored fat.
The research team also found that 51.9% of obesity-induced gene changes in these immune cells remained altered even after weight loss, indicating that the immune cells retained a biological memory of obesity. However, the study revealed that correcting the Scarb1 splicing error with a synthetic genetic patch restored cleanup receptors, increasing inosine availability and enabling the mice to lose fat again.
The findings suggest that specific alternative splicing events in macrophages can shape their phenotypes under certain environmental conditions, potentially paving the way for treatments for people struggling with obesity.
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