U.S. Department of Health and Human Services

Identification of a Protein Controlling Energy Expenditure and Inflammation in Fat Tissue

Researchers have identified a protein in adipose (fat) tissue of mice that regulates both energy expenditure (calorie burning) and inflammation, making it a promising target for treating obesity and type 2 diabetes. Mammals have two major types of fat tissue: brown adipose tissue (BAT) burns fat and thereby increases energy expenditure, and white adipose tissue (WAT), the more abundant form, stores fat. A promising approach to treating obesity and related diseases is to make WAT take on BAT-like characteristics to increase whole-body energy expenditure. Toward this goal, researchers sought to identify factors that regulate energy expenditure. They identified an ion channel protein, TRPV4, that is found in high levels in WAT. In cells grown in laboratory culture, experimentally blocking TRPV4 made WAT become more like BAT by activating genes that increased energy expenditure. Blocking TRPV4 in fat cells was also found to have an unexpected benefit—it decreased the activity of genes important in promoting inflammation. Obesity is associated with chronic, low-grade inflammation of fat tissue, which contributes to the development of insulin resistance, a condition associated with type 2 diabetes; therefore, identifying ways to reduce inflammation is an important goal. These results suggest that TRPV4 regulates both energy expenditure and inflammation in fat tissue, even though scientists previously thought that the molecular mechanisms regulating those processes were distinct. To see if TRPV4 played this dual role in animals, the researchers conducted experiments using mice that were genetically engineered to lack TRPV4. On a regular diet, the experimental mice weighed the same as control mice. However, when the animals were fed a high-fat diet for 16 weeks, the mice lacking TRPV4 not only gained less fat weight than control mice, but were also protected from fat tissue inflammation and insulin resistance. They also had increased energy expenditure without differences in food intake, physical activity, or body temperature compared to control mice, suggesting that the increased energy expenditure was due, at least in part, to increased fat burning. Because these findings suggest that TRPV4 may be a promising drug target for treating obesity, the scientists next used, as a potential drug, a chemical that inhibits TRPV4 activity in obese mice. Compared to control mice, the treated animals had improved glucose tolerance, and their fat tissue showed increased activation of energy burning genes and decreased activation of genes involved in inflammation. These results suggest that inhibiting TRPV4 gives a two-fold benefit of increasing energy expenditure and reducing inflammation in fat tissue. If these findings are extended to humans, targeting the protein may be a therapeutic avenue for treating obesity and type 2 diabetes. 
 
Ye L, Kleiner S, Wu J, et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151: 96-110, 2012.