Weight loss is widely known to lower the risk of metabolic diseases such as type 2 diabetes. But whether losing weight actually restores the health of fat tissue itself has remained an open question.
A new study from the University of Southern Denmark suggests that fat tissue is more resilient than previously thought. Using advanced single-cell analysis, researchers found that weight loss can reverse many of the cellular and inflammatory changes associated with obesity, especially after larger weight reductions.
The study, published in Nature Metabolism, followed people with severe obesity through different stages of weight loss. Participants were evaluated before any intervention, after a moderate 5-10% weight loss achieved through dietary changes, and again two years after bariatric surgery, when weight loss reached 20-45%.
Obesity is known to disrupt fat tissue by increasing inflammation, reducing insulin sensitivity and limiting blood supply. These changes can impair how fat tissue stores and releases energy and contribute to broader metabolic dysfunction. While weight loss reliably improves blood sugar control at the whole-body level, it has been unclear whether fat tissue itself fully recovers.
To answer that question, researchers analyzed subcutaneous fat tissue samples using single-cell sequencing to track changes in cell populations and gene activity over time.
After substantial weight loss, the improvements were pronounced. Immune cells within fat tissue were greatly reduced, with several types returning to levels typically seen in lean individuals. This matters because immune cells drive inflammation that interferes with insulin signaling in fat tissue and can affect metabolism throughout the body.
“When we analyzed the adipose tissue samples taken two years after surgery, following considerable weight loss, the changes were striking,” said Anne Loft, assistant professor at the University of Southern Denmark. “The number of immune cells was greatly reduced — and several types of immune cells were down to levels normally seen in lean individuals.”
The researchers also observed an increase in blood vessel cells, which may improve oxygen and nutrient delivery within fat tissue. Across cell types, gene expression patterns largely normalized, suggesting that obesity-related fat tissue dysfunction is not necessarily permanent.
The findings were more nuanced at the earlier stage of weight loss. Despite clinical evidence that a 5% weight reduction improves insulin sensitivity, the researchers did not observe a clear decrease in inflammation within fat tissue at this point.
“At this stage, we didn’t see a drop in inflammation,” Loft said, indicating that early metabolic improvements are unlikely to be driven by reduced fat tissue inflammation.
Instead, moderate weight loss was associated with an increase in specific precursor fat cells and changes in gene activity that promote the formation of new fat cells.
“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,” said Susanne Mandrup, professor at the University of Southern Denmark. “This suggests that modest weight loss may promote formation of new and healthier fat cells, which may contribute to the improved insulin sensitivity.”
Together, the results challenge the idea that fat tissue retains a lasting “memory” of obesity that cannot be reversed.
“Our study indicates that even modest weight loss in these patients can benefit the health of the fat tissue,” Mandrup said. “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.”
The authors note that the study focused on people with severe obesity and examined subcutaneous fat tissue rather than all fat depots. While the findings cannot be generalized to all populations, they offer new insight into how weight loss reshapes metabolism at the cellular level.
The study was supported by grants from the Danish National Research Foundation to the Center for Functional Genomics and Tissue Plasticity (ATLAS); the Novo Nordisk Foundation; and the Lundbeck Foundation. Imaging and computational resources were supported by multiple bioimaging centers and national research infrastructure programs in Denmark.