Weill Cornell Researchers Uncover Key Protein Linked to Diabetes

Weill Cornell Medicine scientists have made a significant discovery regarding the early stages of fat cell inflammation that could contribute to type 2 diabetes in individuals suffering from obesity. Their findings, published on October 28, 2023, in the Journal of Clinical Investigation, reveal that a protein known as FAM20C acts as a switch, triggering inflammation and insulin resistance in the fat cells of obese mice.

The research indicates that by utilizing genetic techniques to remove or inhibit the FAM20C gene, the metabolic health of the mice improved dramatically. These changes led to a reduction in inflammation and an increase in insulin sensitivity, even without any weight loss. By targeting FAM20C in fat cells, the mice exhibited healthier fat profiles, which significantly diminishes harmful inflammation that often leads to chronic conditions such as type 2 diabetes, fatty liver disease, and heart disease.

Dr. James Lo, the study’s senior author and an associate professor of medicine in the Division of Cardiology at Weill Cornell Medicine, emphasized the implications of the research. He explained that the activation of FAM20C in adipose tissue during obesity results in inflammation, which subsequently drives the expression of other inflammatory genes and leads to insulin resistance.

Research associate Dr. Ankit Gilani, the first author of the study, elaborated on the methodology. The team identified FAM20C while searching for genes activated in fat cells of obese mice experiencing inflammation. FAM20C is classified as a kinase, a type of protein that modifies other proteins by adding phosphate groups, thus influencing their activity. When the team increased FAM20C levels in fat cells, they observed the release of inflammatory molecules and a corresponding rise in insulin resistance. Conversely, eliminating or blocking FAM20C in the mice had a beneficial effect, reducing harmful visceral fat accumulation around the organs.

To explore whether similar inflammatory processes occur in humans, the researchers analyzed visceral fat tissue samples from individuals with obesity. They discovered that elevated levels of FAM20C in these samples correlate with insulin resistance, a pivotal factor in the onset of type 2 diabetes. Notably, individuals who are overweight but exhibit low levels of FAM20C tend to show better metabolic health.

Looking ahead, the research team aims to delve deeper into how FAM20C influences other tissues essential for metabolism. A particular focus will be on a protein known as CNPY4, which is a target of FAM20C and plays a critical role in activating inflammatory genes. Dr. Lo highlighted the potential of CNPY4 as a therapeutic target, expressing interest in determining its influence on insulin resistance.

The ultimate goal of this research is to develop small-molecule therapies that specifically target FAM20C or CNPY4. Such advancements could help block inflammatory responses, treat or prevent type 2 diabetes, reduce visceral fat, and enhance insulin sensitivity. Dr. Lo noted that these therapies may complement weight loss medications and be particularly beneficial for individuals who continue to face inflammation, insulin resistance, and cardiovascular issues post-weight loss.

This groundbreaking study underscores the intricate relationship between fat cell inflammation and metabolic health, paving the way for future research that could lead to innovative treatments for type 2 diabetes and related conditions.