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

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

doi:10.1016/j.cell.2012.08.034

Cited by 296 publications

(322 citation statements)

References 63 publications

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“…Because we found cilia of human TM cells to respond to pressure changes, and OCRL is known to transport membrane bound proteins, we hypothesized that it may interact with a mechanosensory channel within the cilia. TRPV4 is a mechanosensitive calcium-permeable cation channel that localizes to cilia, where it functions in osmotic regulation (32,(37)(38)(39). TRPV4 dysregulation has been implicated in diseases with fluid overload, such as hydrocephalus and heart failure (32,40).…”

Section: Resultsmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

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Section: Resultsmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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“…4 TRPM8 stimulation by menthol increased UCP1 expression in brown adipocytes and BAT through PKA phosphorylation 5 whereas knockdown of TRPV4 facilitated UCP1 expression in 3T3-F442A adipocytes. 6 We recently reported that TRPV2 is more highly expressed in mouse brown adipocytes than TRPV1, TRPV3, TRPV4 and TRPM8. Moreover, the expression of TRPV2 was significantly increased in differentiated brown adipocytes compared with preadipocytes at mRNA, protein and functional levels.…”

mentioning

confidence: 99%

TRPV2 regulates BAT thermogenesis and differentiation

2016

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“…Recent results suggest that transient receptor potential channels may provide a novel means of indirect and direct activation of BAT-dependent thermogenesis. 74,75 As mentioned above, there are compelling data indicating that BAT thermogenesis relies on lipolysis, and that both brown and white adipocytes contribute to the total thermogenic response of lipolytic agents. In view of the failure of ADRB3 agonists to work as thermogenic agonists in humans, other means of activating lipolysis need to be exploited.…”

Section: The Central Role Of Bat In Nonshivering Thermogenesis and Tmentioning

confidence: 99%

Renaissance of brown adipose tissue research: integrating the old and new

Granneman

2015

Int J Obes Supp

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Renaissance of brown adipose tissue research: integrating the old and new JG GrannemanThe recent demonstration of active brown adipose tissue (BAT) in adult humans, along with the discovery of vast cellular and metabolic plasticity of adipocyte phenotypes, has given new hope of targeting adipose tissue for therapeutic benefit. Application of principles learned from the first wave of obesity-related BAT research, conducted 30 years earlier, suggests that the activity and/or mass of brown fat will need to be greatly expanded for it to significantly contribute to total energy expenditure. Although the thermogenic capacity of human brown fat is very modest, its presence often correlates with improved metabolic status, suggesting possible beneficial endocrine functions. Recent advances in our understanding of the nature of progenitors and the transcriptional programs that guide phenotypic diversity have demonstrated the possibility of expanding the population of brown adipocytes in rodent models. Expanded populations of brown and beige adipocytes will require tight control of their metabolic activity, which might be achieved by selective neural activation, tissue-selective signaling or direct activation of lipolysis, which supplies the central fuel of thermogenesis.

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

Cited by 296 publications

References 63 publications

Primary cilia signaling mediates intraocular pressure sensation

Primary cilia signaling mediates intraocular pressure sensation

TRPV2 regulates BAT thermogenesis and differentiation

Renaissance of brown adipose tissue research: integrating the old and new

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