title: TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis.
abstract: PGC1α 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleiner
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Rajan
authors.initials: R
authors.lastname: Sah
authors.forename: Rana K
authors.initials: RK
authors.lastname: Gupta
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.forename: Paul
authors.initials: P
authors.lastname: Cohen
authors.forename: Melin J
authors.initials: MJ
authors.lastname: Khandekar
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.forename: Rina J
authors.initials: RJ
authors.lastname: Mepani
authors.forename: Dina
authors.initials: D
authors.lastname: Laznik
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Xinyi
authors.initials: X
authors.lastname: Song
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050916:TRPV Cation Channels; D015534:Trans-Activators; D014157:Transcription Factors; C486576:Trpv4 protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1