Editors' ChoicePhysiology

Targeting TRPV4 to Treat Metabolic Disease

Sci. Signal.  02 Oct 2012:
Vol. 5, Issue 244, pp. ec253
DOI: 10.1126/scisignal.2003655

There are two kinds of adipose tissue: White adipose tissue stores lipids, and brown adipose tissue dissipates heat by uncoupling mitochondrial activity from adenosine triphosphate synthesis. The transcriptional coregulator PGC-1α [peroxisome proliferator–activated receptor γ (PPARγ), coactivator 1α] and the mitochondrial uncoupling protein UCP1 are abundant in brown adipocytes and can be induced by conditions that stimulate thermogenesis, such as exposure to cold or adrenergic signaling. Ye et al. screened a white adipocyte cell line with a chemical library for compounds that increased the abundance of Pgc1α mRNA and identified an antagonist of the TRPV (transient receptor potential type V) family of calcium channels. TRPV4 was the most abundant of this TRPV family in the adipocyte cell line, and knockdown of TRPV4 increased Pgc1α and Ucp1 mRNA, which suggests that TRPV4 may function to limit the “browning” of white fat. Microarray analysis, confirmed by quantitative reverse transcription polymerase chain reaction, showed that knockdown of TRPV4 also reduced the mRNA abundance and production of proinflammatory cytokines and chemokines in this white adipocyte cell line. Treatment of the cells with a TRPV agonist in the presence of specific inhibitors of mitogen-activated protein kinase pathways indicated that activation of the ERK pathway was necessary for repression of Pgc1α expression by TRPV4. TRPV4-deficient mice exhibited increased UCP1 mRNA and protein in subcutaneous fat. Although, when fed a normal diet, these mice were the same size as wild-type mice, the TRPV4-knockout mice showed less weight gain, had smaller and a greater number of UCP1-positive adipocytes, exhibited increased energy expenditure, and had reduced markers of immune cells in fat tissue. Treatment of diet-induced obese mice with a TRPV4 antagonist increased the expression of thermogenic genes and reduced expression of proinflammatory markers in fat tissue, as well as improved glucose tolerance. Thus, development of TRPV4 antagonists may be an effective strategy in the fight against metabolic disease.

L. Ye, S. Kleiner, J. Wu, R. Sah, R. K. Gupta, A. S. Banks, P. Cohen, M. J. Khandekar, P. Boström, R. J. Mepani, D. Laznik, T. M. Kamenecka, X. Song, W. Liedtke, V. K. Mootha, P. Puigserver, P. R. Griffin, D. E. Clapham, B. M. Spiegelman, TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151, 96–110 (2012). [Online Journal]