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

L. Ye; Sandra Kleiner; Jun Wu; Rajan Sah; Rana K Gupta; Alexander S. Banks; Paul Cohen; Melin J. Khandekar; Pontus Boström; Rina J. Mepani; Dina Laznik; Theodore M. Kamenecka; Xinyi Song; Wolfgang Liedtke; Vamsi K. Mootha; Pere Puigserver; Patrick R. Griffin; David E. Clapham; Bruce M. Spiegelman

doi:10.1016/j.cell.2012.08.034

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

L. Ye, Sandra Kleiner, Jun Wu, Rajan Sah, Rana K Gupta, Alexander S. Banks, Paul Cohen, Melin J. Khandekar, Pontus Boström, Rina J. Mepani, Dina Laznik, Theodore M. Kamenecka, Xinyi Song, Wolfgang Liedtke, Vamsi K. Mootha, Pere Puigserver, Patrick R. Griffin, David E. Clapham, Bruce M. Spiegelman

Research output: Contribution to journal › Article › peer-review

259 Scopus citations

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.

Original language	English (US)
Pages (from-to)	96-110
Number of pages	15
Journal	Cell
Volume	151
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2012.08.034
State	Published - Sep 28 2012

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Ye, L., Kleiner, S., Wu, J., Sah, R., Gupta, R. K., Banks, A. S., Cohen, P., Khandekar, M. J., Boström, P., Mepani, R. J., Laznik, D., Kamenecka, T. M., Song, X., Liedtke, W., Mootha, V. K., Puigserver, P., Griffin, P. R., Clapham, D. E., & Spiegelman, B. M. (2012). TRPV4 Is a Regulator of Adipose Oxidative Metabolism, Inflammation, and Energy Homeostasis. Cell, 151(1), 96-110. https://doi.org/10.1016/j.cell.2012.08.034

Ye, L, Kleiner, S, Wu, J, Sah, R, Gupta, RK, Banks, AS, Cohen, P, Khandekar, MJ, Boström, P, Mepani, RJ, Laznik, D, Kamenecka, TM, Song, X, Liedtke, W, Mootha, VK, Puigserver, P, Griffin, PR, Clapham, DE & Spiegelman, BM 2012, 'TRPV4 Is a Regulator of Adipose Oxidative Metabolism, Inflammation, and Energy Homeostasis', Cell, vol. 151, no. 1, pp. 96-110. https://doi.org/10.1016/j.cell.2012.08.034

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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.",

author = "L. Ye and Sandra Kleiner and Jun Wu and Rajan Sah and Gupta, {Rana K} and Banks, {Alexander S.} and Paul Cohen and Khandekar, {Melin J.} and Pontus Bostr{\"o}m and Mepani, {Rina J.} and Dina Laznik and Kamenecka, {Theodore M.} and Xinyi Song and Wolfgang Liedtke and Mootha, {Vamsi K.} and Pere Puigserver and Griffin, {Patrick R.} and Clapham, {David E.} and Spiegelman, {Bruce M.}",

note = "Funding Information: We thank Drs. Zoltan Arany (Beth Israel Deaconess Medical Center) and Bridget Wagner (The Broad Institute) for help with screen setup and Dr. Kai Cui (Duke University) for assistance with statistical analysis. We are grateful to Drs. Patrick Seale and Chih-Hao Lee for useful discussion. We also thank Yingying Zhang, Diti Bhowmick, and Lingling Dai for technical assistance. L.Y. was supported by the Interdisciplinary Training grant 5R90DK071507. This work was supported by NIH grants DK031405 and DK080261 (B.M.S.). B.M.S., V.K.M., and P.R.G. are consultants and shareholders in Ember Therapeutics, Inc. Publisher Copyright: {\textcopyright} 2012 Elsevier Inc.",

year = "2012",

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doi = "10.1016/j.cell.2012.08.034",

language = "English (US)",

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AU - Ye, L.

AU - Kleiner, Sandra

AU - Wu, Jun

AU - Sah, Rajan

AU - Gupta, Rana K

AU - Banks, Alexander S.

AU - Cohen, Paul

AU - Khandekar, Melin J.

AU - Boström, Pontus

AU - Mepani, Rina J.

AU - Laznik, Dina

AU - Kamenecka, Theodore M.

AU - Song, Xinyi

AU - Liedtke, Wolfgang

AU - Mootha, Vamsi K.

AU - Puigserver, Pere

AU - Griffin, Patrick R.

AU - Clapham, David E.

AU - Spiegelman, Bruce M.

N1 - Funding Information: We thank Drs. Zoltan Arany (Beth Israel Deaconess Medical Center) and Bridget Wagner (The Broad Institute) for help with screen setup and Dr. Kai Cui (Duke University) for assistance with statistical analysis. We are grateful to Drs. Patrick Seale and Chih-Hao Lee for useful discussion. We also thank Yingying Zhang, Diti Bhowmick, and Lingling Dai for technical assistance. L.Y. was supported by the Interdisciplinary Training grant 5R90DK071507. This work was supported by NIH grants DK031405 and DK080261 (B.M.S.). B.M.S., V.K.M., and P.R.G. are consultants and shareholders in Ember Therapeutics, Inc. Publisher Copyright: © 2012 Elsevier Inc.

PY - 2012/9/28

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

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