Weight loss may not immediately return all cells in fatty tissue to their pre-obesity state.
Japanese researchers observed this phenomenon in mice made obese by a high-fat diet. After 12 weeks, the animals were given a lower-fat diet for six weeks. Their weight decreased, but some immune cells in their fatty tissue retained biological traces of past obesity.
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Illustrative image from Pexels
These cells, called macrophages, play the role of cleanup agents. In fatty tissue, they collect and eliminate dead cells. This work is particularly important after weight gain, because fat cells grow larger and some eventually die.
The team discovered that obesity changed the way macrophages prepare the instructions needed for their functioning. A cell first copies part of its DNA into RNA. Before using this copy, it removes certain sections and joins together those it keeps. This step is called splicing.
After weight loss, 51.9% of the genes whose splicing had been altered during obesity still showed these changes. In other words, the macrophages continued to produce some instructions differently. The researchers refer to this as cellular memory, because the trace of obesity remained after weight loss.
This is where CWC22 comes in. This protein normally helps the cell correctly assemble its RNA copies. When this system malfunctioned, an important instruction was improperly prepared. The macrophages then became less effective at absorbing and eliminating dead cells present in fatty tissue.
This defect had another consequence. By clearing away dead cells, macrophages help make inosine available, a small molecule that promotes the release of stored fat. When CWC22 function was disrupted, this cleanup decreased, as did the amount of available inosine. In the affected mice, fat loss then became more difficult.
The researchers subsequently attempted to directly correct one of these improperly assembled instructions. They used a short molecule designed to act on RNA. The clearance of dead cells improved, more inosine became available again, and the mice lost more fat. Part of this cellular memory can therefore be experimentally modified.
In humans, the results are still preliminary. The researchers compared fatty-tissue samples from lean people and people living with obesity. CWC22 was less abundant in the nuclei of macrophages from the second group. The team must now determine whether these changes also persist after weight loss.