Weight loss normalizes fat tissue at cellular level

It is well known that obesity typically leads to inflammation and dysfunction of fat tissue that increases the risk of developing metabolic diseases such as diabetes and cardiovascular diseases.

It is also well established that weight loss reduces the risk of developing these diseases. However, it has been unclear whether healthy fat tissue can be reestablished by weight loss. In other words, does fat tissue retain a "memory" of the obese state after weight loss?

Now, a new study led by Assistant Professor Anne Loft, Associate Professor Jesper Grud Skat Madsen, and Professor Susanne Mandrup from University of Southern Denmark sheds light on what happens in the fat tissue during weight loss. The study is published in Nature Metabolism and can be found here: https://www.nature.com/articles/s42255-025-01433-4

All three are leading researchers at the Center of Excellence ATLAS, which investigates the molecular mechanisms driving changes in liver and fat tissues in response to obesity and weight loss. This knowledge is important because obesity-induced dysfunction in these two tissues drive the development of metabolic diseases, such as diabetes and cardiovascular diseases.

Using advanced single-cell analyses, the researchers have now carefully analyzed the cellular and molecular changes in fat tissue from patients with severe obesity at three key stages:

1. When patients were first scheduled for gastric bypass surgery.
2. After a moderate weight loss of 5–10% through dietary changes, just before surgery.
3. Two years post-surgery, after substantial weight loss of 20–45%.

Anne Loft explains:

"When we analyzed the adipose tissue samples taken two years after surgery, following considerable weight loss, the changes were striking. The number of immune cells was greatly reduced – and several types of immune cells were down to levels normally seen in lean individuals. This is one of the most important improvements after weight loss because immune cells contribute to inflammation and reduced insulin sensitivity in fat tissue. This local insulin resistance can affect the whole body and, over time, increase the risk of type 2 diabetes and other obesity-related diseases. So when inflammation and immune cells decrease, it's a clear benefit for health."

The researchers also observed a significant increase in blood vessel cells, which likely helps deliver oxygen and nutrients more efficiently to fat tissue - another positive adaptation. Moreover, gene expression in all cell types was normalized to the lean state.

But what about the moderate weight loss phase? Clinically, it's known that even a 5% drop in weight improves whole-body insulin sensitivity. So, the team examined the corresponding fat tissue.

"At this stage, we didn't see a drop in inflammation," says Loft. "meaning that the improvements in insulin sensitivity is unlikely to be driven by reduced inflammation in fat tissue."

According to Susanne Mandrup, it has long been known that modest weight losses yield health benefits, but it has been unclear whether the health of the fat tissue itself is also improved.

"Using single cell technologies, we saw an increase in a specific type of pre-fat cell and a boost in gene activity promoting the creation of new fat cells," Mandrup explains. "This suggests that modest weight loss may promote formation of new and healthier fat cells, which may contribute to the improved insulin sensitivity."

She concludes:

"Our study indicates that even modest weight loss in these patients can benefit the health of the fat tissue. After major weight loss, the fat tissue largely resemble that of lean individuals, suggesting that the 'memory' of obesity is not as persistent as previously thought"