Biological memory of cells hinders weight loss after obesity

A team of researchers from Japan studied adipose tissue macrophages (ATM) in mice. These cells are important for the health of adipose tissue; in particular, they remove dead cells from there (this process is called efferocytosis).

The experiment consisted of two stages. First, the mice were given a high‑fat diet for 12 weeks — until obesity developed. Then, for 6 weeks, they were switched to a low‑fat diet, simulating an attempt to lose weight.

It turned out that the mice that lost weight the worst were those whose ATM cells had less CWC22 protein in their nuclei. This led scientists to believe that CWC22 plays a role in the body’s ability to lose fat. To test the role of CWC22, scientists created genetically modified mice in which the gene was knocked out in cells that include macrophages. CWC22 is involved in mRNA splicing — the process by which RNA is edited before proteins are synthesized from it.

In such mice, the efferocytosis was disrupted against the background of a weight‑loss diet: macrophages could not effectively remove dead cells from adipose tissue. The reason turned out to be an error in the splicing of the Scarb1 gene: due to it, macrophages destroyed their own clearance receptors even before they reached the cell surface.

Because of poor clearance of adipose tissue, macrophages released less inosine — a substance that serves as a signal for fat cells to break down stored fat. Less inosine means worse fat breakdown.

The key point is that 51.9 % of the genes in these immune cells, which changed due to obesity, remained in an altered state even after weight loss. In other words, the cells retained a biological memory of obesity, and this memory maintained disruptions in their function.

An important discovery is that at least one element of this memory could be corrected. When experts corrected the splicing error in the Scarb1 gene using a synthetic “genetic patch,” the clearance receptors were restored, the level of inosine increased, and the mice began to lose fat again. This shows that some consequences of macrophage memory are potentially reversible.

When the team analyzed tissue samples from lean people and people with obesity, the picture turned out to be similar: in the nuclei of immune cells from lean people, a lot of CWC22 was detected, while in people with obesity, less was found. This suggests that the described mechanism may also work in humans.