Scientists Discover Key Protein Triggering Inflammation Linked to Obesity and Type 2 Diabetes

Key Takeaways:

• Researchers have identified FAM20C as a protein that triggers inflammation and insulin resistance in fat cells, a process linked to type 2 diabetes.
  
• Blocking or removing the FAM20C gene in mice improved insulin sensitivity and reduced inflammation, even without weight loss.
  
• High levels of FAM20C in human fat tissue are associated with insulin resistance, suggesting a potential new therapeutic target.
  
  

Early trigger identified in obesity-related inflammation

Investigators at Weill Cornell Medicine have uncovered an early step in the chain of events that links obesity to inflammation and insulin resistance – key contributors to the development of type 2 diabetes.

Their findings, published on 28 October in the Journal of Clinical Investigation, identify a protein known as FAM20C as a critical “switch” that initiates inflammation within fat cells. The study, conducted in mice, shows that when this protein is removed or blocked, metabolic health improves markedly, even without weight loss.

“By inhibiting or getting rid of FAM20C in fat cells, the mice became healthier even at the same body weight,” said senior author Dr James Lo, the Rohr Family Clinical Scholar and an Associate Professor of Medicine in the Division of Cardiology at Weill Cornell Medicine. “Their fat becomes metabolically healthier, reducing harmful inflammation in fat cells that can lead to chronic diseases like type 2 diabetes, fatty liver disease and heart disease.”

FAM20C: A molecular switch for inflammation

The research team, led by first author Dr Ankit Gilani, a Research Associate in Medicine at Weill Cornell Medicine, discovered FAM20C while screening genes that were switched on in the fat cells of mice with obesity and inflammation. FAM20C belongs to a class of enzymes known as kinases, which work by adding phosphate groups to other proteins – a process that can alter their activity and influence gene expression.

When the researchers increased the production of FAM20C in fat cells, the cells began releasing inflammatory molecules and became resistant to insulin. In contrast, blocking or deleting the gene in mice with obesity had the opposite effect – it reduced inflammation, improved insulin sensitivity, and decreased the accumulation of visceral fat (fat surrounding internal organs), even when total body weight remained unchanged.

“During obesity, when this gene is switched on in the adipose tissue, it causes inflammation,” Dr Gilani explained. “It drives the expression of other inflammatory genes, and then it causes insulin resistance, which can lead to type 2 diabetes.”

Evidence from human fat tissue

To determine whether the same mechanism operates in humans, the researchers analysed visceral fat tissue samples from individuals living with obesity. They found that higher levels of FAM20C were associated with insulin resistance – a key driver of type 2 diabetes – while people with lower FAM20C levels tended to exhibit better metabolic health despite having overweight or obesity.

These findings suggest that the FAM20C pathway could play a pivotal role in determining whether fat tissue becomes inflamed and metabolically harmful or remains relatively benign.

Next Steps: Targeting FAM20C and its downstream pathways

The research team now plans to investigate how FAM20C influences other tissues involved in metabolism and metabolic disease. They are particularly interested in a protein called CNPY4, which is activated by FAM20C and appears to be central to the inflammatory process.

“CNPY4 is going to be a major focus of future research to see how strongly it affects insulin resistance, and whether it could be a target for therapies to treat or prevent insulin resistance,” said Dr Lo, who is also a member of the Weill Center for Metabolic Health and the Cardiovascular Research Institute at Weill Cornell Medicine, and a cardiologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Ultimately, the team hopes to develop small-molecule drugs that can block FAM20C or CNPY4 activity. Such therapies could reduce inflammation, lower visceral fat levels, improve insulin sensitivity, and help prevent or treat type 2 diabetes. Dr Lo noted that these treatments might one day be used alongside weight loss medications, or to support people who continue to experience metabolic inflammation and cardiovascular risk even after losing weight.

Funding and support

This research was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH), through grants R01DK121140 and R01DK121844.

CCH insights

For a long time now we have known that inflammation in visceral adipose tissue is a major factor in insulin resistance, but it is still unknown why some people with obesity experience this adipose tissue inflammation and subsequent metabolic dysfunction, while other people with obesity do not. This research suggests that the FAM20C protein may contribute to this switch from healthy adipose tissue to inflamed, dysfunctional adipose tissue, and could offer an exciting new therapeutic pathway for type 2 diabetes and other cardiometabolic conditions.