U.S. Department of Health and Human Services

Suppression of Fat Tissue Inflammation Promotes Insulin Sensitivity

Scientists have uncovered a key factor in the link between obesity and type 2 diabetes. Insulin resistance is a condition in which the body produces the hormone insulin but does not use it properly. Because this condition leads to increased risk for type 2 diabetes and heart disease, understanding how insulin resistance develops is critical toward efforts to prevent or reverse it. During excess weight gain, a type of immune cell migrates into and accumulates in adipose (fat) tissue and promotes chronic, low grade inflammation, which contributes to the development of insulin resistance. Another type of immune cell, the regulatory T cell (Treg), is abundant in the adipose tissue of lean, but not overweight, mice and humans. The presence of Tregs in adipose tissue helps to protect mice from developing insulin resistance. However, the molecular mechanisms that regulate the Treg cell population in adipose tissue remained undefined. 
 
In a recent study, researchers found that a protein known to be essential for fat cell development is also critical for maintaining adipose tissue Treg cell numbers in mice. The protein, called PPAR γ, resides within adipose tissue Tregs, as well as within fat cells themselves. PPAR-γ controls the activities of different sets of genes, depending on the particular cell type. The scientists genetically engineered mice to lack PPAR-γ exclusively in Tregs, and observed a significant reduction in Treg cell numbers within adipose tissue. Pioglitazone, an insulin sensitizing drug used to treat type 2 diabetes, is known to activate PPAR-γ. The researchers thus sought to understand whether PPAR-γ in Tregs was responsible for pioglitazone’s insulin sensitizing effects. To test this idea, the scientists treated obese mice with pioglitazone, and observed an increase in Treg cells in adipose tissue, suggesting that the drug treatment can influence the abundance of adipose tissue Treg cells. In these mice, pioglitazone treatment improved metabolic traits such as insulin resistance, glucose tolerance, and insulin tolerance. However, in mice that lacked PPAR-γ in Treg cells, pioglitazone did not increase the abundance of adipose tissue Tregs and improved metabolic traits were not observed. These findings reveal a new role for PPAR-γ in suppressing adipose tissue inflammation by recruiting Tregs to adipose tissue. This study also defines a new molecular pathway for pioglitazone action—one that might be exploited to develop new and effective therapeutics for type 2 diabetes. 
 
Cipolletta D, Feuerer M, Li A, et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486: 549 553, 2012