Scientists discovered that a protein called Sirt6 helps control immune cells in your body, and when you gain weight, this protein decreases. When Sirt6 levels drop, immune cells called mast cells start causing inflammation and damage to fat tissue, making obesity worse. Researchers found that another protein called galectin-3 is the troublemaker behind this process. The good news? If they blocked galectin-3, the harmful effects disappeared. This discovery suggests new ways to treat obesity-related health problems by targeting these specific proteins in immune cells.

The Quick Take

  • What they studied: How a protein called Sirt6 in immune cells affects weight gain, inflammation, and metabolic problems in obesity
  • Who participated: Laboratory mice (both male and female) and human tissue samples from people with obesity; the study used genetic modifications to remove or add specific proteins
  • Key finding: When Sirt6 protein is missing from mast cells (a type of immune cell), mice gained significantly more weight on a high-fat diet and developed worse inflammation and tissue damage. This effect disappeared when another protein called galectin-3 was also removed, suggesting galectin-3 is the key problem.
  • What it means for you: This research suggests that future treatments targeting galectin-3 or boosting Sirt6 in immune cells could help prevent obesity-related complications like inflammation and insulin resistance. However, this is early-stage research, and human treatments are not yet available.

The Research Details

This was a laboratory research study using genetically modified mice to understand how specific proteins control immune cell behavior during obesity. Researchers created mice lacking the Sirt6 protein in mast cells and compared them to normal mice fed a high-fat diet. They also performed a technique called adoptive transfer, where they took immune cells from one group of mice and transplanted them into another group to test their effects. Additionally, researchers used advanced genetic sequencing technology to examine individual immune cells and identify which ones were causing problems.

The study combined multiple approaches: genetic manipulation (removing or keeping proteins), dietary intervention (high-fat diet), cell transplantation experiments, and detailed molecular analysis. This multi-layered approach helped researchers understand both what happens and why it happens at the cellular level.

Human tissue samples were also examined to confirm that the findings from mice apply to real people with obesity, making the research more relevant to human health.

This research approach is important because it goes beyond just observing what happens in obesity—it actually proves cause-and-effect relationships. By removing specific proteins and seeing what changes, scientists can identify which proteins are truly responsible for problems. This is much more powerful than just noticing that certain proteins are lower in obese people. The cell transplantation experiments were particularly clever because they proved that the immune cells themselves, not other body systems, were causing the weight gain and inflammation.

This study was published in Nature Communications, a highly respected scientific journal that requires rigorous peer review. The research used multiple complementary methods (genetic studies, cell transplants, and advanced sequencing), which strengthens confidence in the findings. The fact that human tissue samples showed similar patterns to mouse studies suggests the results are likely relevant to people. However, the study was conducted in laboratory mice, not humans, so results may not translate perfectly to real-world human treatment.

What the Results Show

When researchers removed the Sirt6 protein from mast cells in mice, those mice gained significantly more weight when eating a high-fat diet compared to normal mice. The mice with missing Sirt6 also developed worse inflammation in their fat tissue and more scarring (fibrosis), which damages the tissue’s ability to function properly.

When researchers transplanted mast cells without Sirt6 into mice that naturally lack mast cells, those mice gained more weight than mice that received normal mast cells. This proved that the problem came from the immune cells themselves, not from other body systems.

The breakthrough came when researchers removed both Sirt6 and galectin-3 from the mast cells. In this case, the harmful effects disappeared—mice didn’t gain extra weight, and inflammation didn’t worsen. This showed that galectin-3 is the actual troublemaker, and Sirt6 normally prevents problems by controlling galectin-3 production.

At the molecular level, Sirt6 works by modifying a chemical tag on DNA at the galectin-3 gene, essentially turning down the volume on galectin-3 production. When Sirt6 is missing, galectin-3 production increases, triggering a cascade of inflammatory problems.

Advanced genetic sequencing revealed that in obese mice lacking Sirt6, a specific subpopulation of mast cells dominated the fat tissue—cells that were particularly good at causing inflammation and tissue damage. These problematic mast cells were much less common in normal mice. The research also showed that galectin-3 promotes the transformation of immune cells called macrophages into a pro-inflammatory form (M1 macrophages), which actively damage tissue. Additionally, the study confirmed that Sirt6 levels naturally decrease in both obese mice and obese humans, suggesting this is a real biological response to weight gain that could be targeted therapeutically.

Previous research had established that mast cells play a role in obesity and that inflammation in fat tissue contributes to insulin resistance and metabolic problems. However, the specific mechanisms—how mast cells cause these problems and which proteins are responsible—were unclear. This study fills that gap by identifying Sirt6 and galectin-3 as key players. The findings align with other research showing that Sirt6 is a protective protein in various tissues, but this is among the first to demonstrate its specific role in immune cells during obesity. The discovery that blocking galectin-3 can reverse the harmful effects of missing Sirt6 is novel and opens new therapeutic possibilities.

This research was conducted entirely in laboratory mice with genetic modifications, not in living humans. While human tissue samples were examined, actual human studies would be needed to confirm these findings apply to real people. The study doesn’t explain why Sirt6 levels naturally decrease during obesity—whether it’s a cause or a consequence. Additionally, the research focused on mast cells specifically; other immune cells may have different roles in obesity that weren’t explored. The study also doesn’t address whether these findings apply equally to men and women, or to different types of obesity. Finally, no human treatments have been tested yet, so it’s unknown whether targeting these proteins would actually help people lose weight or improve their health.

The Bottom Line

Based on this research, future medical treatments might target galectin-3 or boost Sirt6 activity in immune cells to reduce obesity-related inflammation and metabolic problems. However, these treatments don’t exist yet for human use. Current evidence-based recommendations for obesity remain: maintain a balanced diet, exercise regularly, and consult healthcare providers for personalized guidance. This research suggests why obesity causes inflammation and metabolic damage, which reinforces the importance of weight management, but it doesn’t change current treatment approaches.

This research is most relevant to people with obesity who struggle with inflammation, insulin resistance, or metabolic syndrome. It’s also important for researchers developing new obesity treatments and for healthcare providers treating obesity-related complications. People without obesity don’t need to take action based on this research. Those with genetic conditions affecting mast cells or immune function should discuss this research with their doctors, though it’s too early to change treatment based on these findings alone.

This is fundamental research that explains biological mechanisms. Actual treatments targeting these proteins are likely years away from human testing. If such treatments are developed, it would typically take 5-10 years of clinical trials before becoming available to patients. In the meantime, people should focus on proven weight management strategies while scientists work on developing new therapies based on this research.

Want to Apply This Research?

  • Track weekly weight, waist circumference, and energy levels. Also monitor inflammatory markers if available through medical testing (like C-reactive protein). This creates a baseline to measure if future treatments targeting these immune pathways become available.
  • Use the app to log high-fat food intake and correlate it with energy levels and inflammation symptoms (joint pain, fatigue, swelling). This helps users understand their personal response to diet and prepares them to recognize benefits if future immune-targeted treatments become available.
  • Establish a 12-week tracking period measuring weight, diet quality, exercise, and subjective inflammation markers. Share results with healthcare providers to identify patterns and discuss whether future research-based treatments might be appropriate as they become available.

This research describes laboratory findings in mice and is not yet applicable to human treatment. The proteins and pathways described (Sirt6, galectin-3) are not currently targeted by approved human medications for obesity. Anyone with obesity or metabolic concerns should consult with their healthcare provider about evidence-based treatments available today. This article is for educational purposes and should not be interpreted as medical advice or a recommendation to seek specific treatments. Future therapies based on this research may eventually become available, but human clinical trials would be required before any new treatments could be used in medical practice.