Person:

Ye, Li

(PGC1\alpha) is a key transcriptional coregulator of mitochondrial biogenesis, oxidative metabolism and thermogenesis. We developed a quantitative high throughput screen to identify small molecules that can induce (PGC1\alpha) expression in adipocytes. Small molecules antagonizing the TRPVs (Transient Receptor Potential Vanilloid), a family of ion channels, induced (PGC1\alpha) expression in adipocytes. In particular, inhibition of TRPV4 increased expression of (PGC1\alpha), UCP1 and cellular respiration; conversely, chemical activation of TRPV4 repressed this pathway. Blocking TRPV4 in cultured adipocytes also reduced the expression of multiple proinflammatory genes that are involved in the development of insulin resistance. These effects of TRPV4 were mediated by the activation of ERK1/2. Finally, mice with a null mutation for TRPV4 showed higher energy expenditure with no change in movement or food intake, and were protected from diet-induced obesity, adipose inflammation and insulin resistance. This study links TRPV4 to robust pathways that offer therapeutic potential in obesity and related metabolic diseases.