As people age, many gradually realize that there seems to be more and more fat on their bellies. It starts as an unnoticeable small piece of fat and gradually turns into a "love handle." In places invisible to the naked eye, such as around the liver, visceral adipose tissue tends to accumulate easily. "Fatty liver" is also a common problem in the medical examination reports of middle-aged people. But why does fat accumulate uncontrollably when people reach their thirties or forties, and why is it almost inevitable for the body to experience "weight gain"?

Some people may think that the decline in metabolic level is the key factor driving fat accumulation. However, in 2021, a paper in the journal Science found through large-scale measurements of energy expenditure levels that the human metabolic level doesn't really start to decline until after the age of 60. Therefore, this factor doesn't seem to be the culprit for middle-aged weight gain.

Now, a study published in the latest issue of the journal Science has discovered a completely different perspective: As people reach middle age, the ability to generate fat cells becomes stronger. This special change is closely related to the activity of adipose progenitor cells (APCs). APCs will continuously generate new fat cells in middle-aged individuals and promote the expansion of adipose tissue, leading to the accumulation of a large amount of fat in various parts of the body.

There are mainly two ways for the increase of individual adipose tissue, including the hypertrophy of fat cells (increase in cell volume) and adipogenesis (generation of new fat cells). Previous studies generally believed that, like other stem cells, the proliferative ability of APCs would gradually decline with individual aging, thus reducing the number of fat cells.

However, the phenomenon observed by the researchers in mice was exactly the opposite. They analyzed the changes in the body fat of a group of male mice that were on a normal diet and were 12 months old (equivalent to about 45 years old in humans). The results showed that compared with younger mice, the body weight of these mice was significantly heavier, and the weight of adipose tissue increased significantly. The visceral fat increased by 4.6 times relatively, and the subcutaneous fat increased by 2.8 times. At the same time, more than 80% of the fat cells in the visceral adipose tissue were newly generated. Under the same conditions, the weight and fat gain in female mice were relatively mild, which also explains to some extent why men are usually more prone to "weight gain" in middle age.

The researchers analyzed the adipose tissue of male middle-aged mice through single-cell RNA sequencing technology and found a new subset of adipose progenitor cells - CP-A cells. These cells start to appear when the mice are 9 months old and reach their peak at 12 months old. In addition to a sharp increase in number, CP-A cells also maintain a strong ability to proliferate and differentiate, which leads to particularly active fat cell generation.

In addition, the researchers found that the APCs of middle-aged individuals have an inherent potential to promote obesity. They tried to transplant these cells into young mice, and as a result, the young mice also started to gain weight and showed a trend of "weight gain." The authors speculated that APCs may have a different response mechanism from other stem cells. When adipose tissue starts to age, it will instead activate the "impulse" of APCs to compensate for the aging cells.

In human adipose tissue, the authors found a cell subset similar to CP-A, whose cell characteristics and behaviors are very similar to those found in mice, indicating that human adipose stem cells may also undergo similar changes in middle age.

What's worth looking forward to is that the new study may also bring feasible strategies to solve middle-aged weight gain. After analyzing the activation mechanism of CP-A cells, they found a unique and essential molecule - leukemia inhibitory factor receptor LIFR. This protein receptor is not only highly expressed in CP-A cells but also crucial for adipogenesis. After inhibiting LIFR with drugs, the adipogenesis of CP-A cells in middle-aged individuals can be significantly reduced, but this strategy does not affect the adipogenic ability of APCs in young mice.

If the inhibition time of LIFR is precisely controlled, for example, by intervening in mice in the early stage of aging, then the visceral fat accumulation in middle-aged mice can be prevented in the long term. This discovery provides new ideas for the prevention and treatment of middle-aged obesity and related metabolic diseases. Perhaps in the future, "middle-age spread" will no longer be a concern for middle-aged people.