Scientists discovered that a protein called uPA (urokinase plasminogen activator) plays an important role in how our bodies gain weight and develop weight-related health problems. When researchers removed this protein from mice, the animals gained less weight and had fewer metabolic problems when eating a high-fat diet—at least for the first 14 weeks. Interestingly, the protein’s role in immune cells called macrophages wasn’t the main driver of weight gain. This finding could eventually help scientists develop new treatments for obesity and related diseases like fatty liver disease and diabetes, though much more research is needed before any treatments could help people.

The Quick Take

  • What they studied: Whether a protein called uPA (found in immune cells and fat tissue) contributes to weight gain and obesity-related health problems when eating a high-fat diet
  • Who participated: Laboratory mice with different genetic modifications (some without uPA, some with normal uPA) and human fat tissue samples from people who had weight-loss surgery
  • Key finding: Mice completely lacking the uPA protein gained significantly less weight and had fewer metabolic problems over 14 weeks on a high-fat diet compared to normal mice, though this advantage disappeared with longer feeding periods
  • What it means for you: This research suggests uPA may be a target for future obesity treatments, but it’s very early-stage laboratory work. Don’t expect any immediate medical applications—scientists need to do much more research to understand if this works in humans and how to safely target this protein

The Research Details

This study combined human tissue analysis with laboratory mouse experiments. First, researchers examined fat tissue from people who had weight-loss surgery and found that uPA protein levels were higher in people with obesity and decreased after surgery. Then they created special laboratory mice—some completely lacking the uPA protein and others lacking it only in immune cells—and fed them either normal or high-fat diets for up to 20 weeks. They measured weight gain, metabolic markers, and other health indicators throughout the study.

The researchers used this approach because mice are useful for understanding biological mechanisms before testing in humans. By creating mice with selective deletions of the uPA protein, they could determine which cells and tissues were most important for uPA’s effects on weight gain.

This type of experimental design allows scientists to establish cause-and-effect relationships that wouldn’t be possible in human studies, where researchers can only observe and measure rather than manipulate genes.

Understanding which proteins drive obesity is crucial because obesity affects hundreds of millions of people worldwide and increases risk for serious diseases. By identifying uPA’s role, scientists can potentially develop drugs that target this specific pathway. The study’s approach of testing both global and selective protein removal helps clarify whether uPA’s effects come from immune system dysfunction or other mechanisms.

This research was published in a peer-reviewed journal focused on vascular and metabolic biology, suggesting it met scientific standards for publication. The study used well-established laboratory techniques and included both human tissue analysis and animal models. However, the sample size for human tissue wasn’t specified, and the findings in mice don’t automatically translate to humans. The fact that the protective effect disappeared with prolonged high-fat feeding suggests the relationship is more complex than initially apparent.

What the Results Show

In human tissue samples, uPA protein levels were significantly higher in fat tissue from people with obesity compared to those without obesity. After people underwent weight-loss surgery, their uPA levels decreased substantially over two years, suggesting the protein is connected to excess weight.

In mice, the results were striking but time-dependent. Mice completely lacking uPA gained about 30-40% less weight than normal mice during the first 14 weeks on a high-fat diet and showed better metabolic health markers. However, this advantage largely disappeared by week 20, suggesting that either the mice’s bodies adapted or other mechanisms compensated for the missing protein.

Surprisingly, when researchers removed uPA only from immune cells (macrophages), the mice still gained weight normally and developed metabolic problems just like regular mice. This finding was unexpected because scientists thought immune cell dysfunction was the main problem in obesity.

These results suggest that uPA’s role in obesity involves mechanisms beyond just immune cell function, possibly involving how fat cells themselves behave or how the body processes nutrients.

The study found that uPA expression and activity increased in fat tissue of mice eating high-fat diets, indicating the protein becomes more active when consuming unhealthy diets. The correlation between uPA levels and body mass index in human patients was consistent across the study population, suggesting this relationship is reliable. The metabolic improvements in uPA-deficient mice included better glucose control and reduced inflammation markers, indicating benefits beyond just weight reduction.

Previous research established that uPA helps immune cells move through tissues and that inflammation in fat tissue drives obesity. This study builds on that knowledge by showing uPA’s specific role in obesity development. However, the finding that removing uPA from immune cells alone didn’t prevent obesity contradicts some earlier assumptions about how obesity develops. This suggests the scientific understanding of obesity mechanisms needs refinement.

The study’s main limitation is that it was conducted in laboratory mice, which don’t perfectly replicate human biology or behavior. The human tissue samples were limited in number and came only from people undergoing weight-loss surgery, which may not represent the general population. The protective effect of uPA deletion disappeared after 14 weeks, raising questions about whether this approach would work long-term in humans. The study didn’t identify exactly which cells or tissues (other than immune cells) are responsible for uPA’s effects on weight gain. Finally, the researchers didn’t test any potential drugs or treatments—only genetic deletion—so it’s unclear whether pharmaceutical approaches would work similarly.

The Bottom Line

Based on this research alone, there are no specific recommendations for people. This is fundamental research aimed at understanding obesity mechanisms, not a study testing treatments. However, the findings suggest that future drug development targeting uPA might help prevent or slow obesity development. Confidence level: Low to moderate, as this is early-stage laboratory research that hasn’t been tested in humans.

This research is most relevant to scientists studying obesity, pharmaceutical companies developing new treatments, and people at high risk for obesity-related diseases who might eventually benefit from new therapies. It’s less immediately relevant to the general public, though the findings may eventually lead to new treatment options. People should not attempt to modify uPA levels themselves, as this protein has multiple functions in the body.

If this research leads to drug development, it would typically take 5-15 years before any treatment could be tested in humans and potentially approved for medical use. Even then, the benefits might be modest or work only in certain populations. This is a very long-term research direction.

Want to Apply This Research?

  • Users interested in obesity research could track their weight weekly and metabolic markers (if available through their healthcare provider) such as fasting glucose and cholesterol levels to monitor their own metabolic health trends over time, providing personal context for understanding research like this
  • While this specific research doesn’t yet translate to actionable changes, users could use the app to track high-fat diet consumption and monitor how it correlates with their weight and energy levels, building awareness of personal diet-health connections that align with the study’s focus on high-fat diet effects
  • Establish a baseline measurement of weight and available metabolic markers, then track monthly to identify personal trends. This long-term data collection helps users understand their individual response to diet and lifestyle changes, providing context for evaluating future obesity-related research and treatments

This research is preliminary laboratory work conducted in mice and has not been tested in humans. The findings do not constitute medical advice or recommendations for treatment. Anyone concerned about obesity, weight gain, or metabolic health should consult with their healthcare provider about evidence-based treatment options currently available. Do not attempt to modify uPA levels or seek uPA-targeting treatments outside of clinical trials, as this protein has multiple important functions in the body and unintended consequences could occur. This summary is for educational purposes only and should not replace professional medical guidance.