Weill Cornell scientists discover early step in fat cell inflammation leading to diabetes

Weill Cornell Medicine investigators have identified an early step in a cellular process that leads to inflammation in fat cells and may result in type 2 diabetes in people with obesity.

The findings, published Oct. 28 in the Journal of Clinical Investigation, show that a protein called FAM20C acts as a switch that turns on inflammation and insulin resistance in the fat cells of overweight mice. Genetic techniques to remove or block the FAM20C gene in animals improved their metabolic health, reduced inflammation and increased insulin sensitivity, even when the animals lost no weight.

By inhibiting or getting rid of FAM20C in fat cells, the mice became healthier even at the same body weight. 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."

Dr. James Lo, study's senior author, the Rohr Family Clinical Scholar and associate professor of medicine, Division of Cardiology, Weill Cornell Medicine

The study's first author, Dr. Ankit Gilani, a research associate in medicine at Weill Cornell Medicine, explained that the team identified FAM20C in a search for genes that were turned on in fat cells in mice with obesity and inflammation. FAM20C is a type of protein called a kinase that adds a phosphate group to other proteins, which changes their activity, and can result in specific genes being turned on.

Next, they found that when they used genetic techniques to increase FAM20C production in fat cells, the cells released inflammatory molecules and became insulin resistant. Knocking out or blocking FAM20C in mice with obesity had the opposite effect. The loss of the protein also reduced the amount of harmful visceral fat—fat that accumulates around the organs—in the mice, even when they did not lose any weight.  

"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."

To see whether the protein sets off a similar cascade of inflammation and disease in humans, the team analyzed visceral fat tissue samples from humans with obesity. They found that elevated FAM20C levels in these cells are linked with insulin resistance, a major driver of type 2 diabetes. Conversely, evidence shows that people who are overweight with low FAM20C levels have better metabolic health.

Next, the team plans to study how the protein, which activates proteins and protein fragments secreted by fat cells, affects other tissues that play important roles in metabolism and metabolic diseases. They particularly want to learn more about a protein called CNPY4, a FAM20C target that plays a pivotal role in activating inflammatory genes.

"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's goal is to create small-molecule therapies targeting FAM20C or CNPY4 that block their inflammatory effects to treat or prevent type 2 diabetes, reduce visceral fat, improve insulin sensitivity and improve blood sugar control in humans. Such therapies might be used along with weight loss medications or to help individuals who continue to experience inflammation, insulin resistance and cardiovascular disease after weight loss, Dr. Lo said.