TRPV4 Is a Regulator of Adipose Oxidative Metabolism, Inflammation, and Energy Homeostasis

SummaryPGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases.

Graphical AbstractFigure optionsDownload high-quality image (196 K)Download as PowerPoint slideHighlights
► TRPV4 is a negative regulator of PGC1α and its thermogenic targets in adipocytes
► TRPV4 positively controls proinflammatory gene expression in adipocytes
► TRPV4 deficiency protects mice from diet-induced obesity and insulin resistance
► Pharmacological inhibition of TRPV4 provides metabolic benefits in obese mice