Involvement of TRPV1 Channels in Energy Homeostasis

Abstract

The ion channel TRPV1 is involved in a wide range of processes including nociception, thermosensation and, more recently discovered, energy homeostasis. Tightly controlling energy homeostasis is important to maintain a healthy body weight, or to aid in weight loss by expending more energy than energy intake. TRPV1 may be involved in energy homeostasis, both in the control of food intake and energy expenditure. In the periphery, it is possible that TRPV1 can impact on appetite through control of appetite hormone levels or via modulation of gastrointestinal vagal afferent signaling. Further, TRPV1 may increase energy expenditure via heat production. Dietary supplementation with TRPV1 agonists, such as capsaicin, has yielded conflicting results with some studies indicating a reduction in food intake and increase in energy expenditure, and other studies indicating the converse. Nonetheless, it is increasingly apparent that TRPV1 may be dysregulated in obesity and contributing to the development of this disease. The mechanisms behind this dysregulation are currently unknown but interactions with other systems, such as the endocannabinoid systems, could be altered and therefore play a role in this dysregulation. Further, TRPV1 channels appear to be involved in pancreatic insulin secretion. Therefore, given its plausible involvement in regulation of energy and glucose homeostasis and its dysregulation in obesity, TRPV1 may be a target for weight loss therapy and diabetes. However, further research is required too fully elucidate TRPV1s role in these processes. The review provides an overview of current knowledge in this field and potential areas for development.

Keywords: TRPV1; appetite regulation; endocannabinoid; endovanilloid; metabolism; obesity.

Figure 1

Structure of a TRPV1 subunit. (A) N-terminus containing 6 ankyrin subunits (A1–A6) and a linking region consisting of a linker and a Pre-S1 helix segment. (B) Transmembrane region with 6 helical segments (S1–S6). (C) C-terminus containing a TRP domain and binding sites for PKA, PKC, PIP₂, and calmodulin.

Figure 2

Schematic of the synthesis, degradation and action of endocannabinoids at cannabinoid receptors. Endogenous lipid messengers, such as AEA and 2-AG, act on cannabinoid receptors. AEA and 2-AG are synthesized on demand and degraded by cellular uptake and enzymatic hydrolysis by FAAH and MAGL respectively. FABP carries AEA from the cell membrane to the endoplasmic reticulum where it is finally converted to AA by FAAH. AA, arachidonic acid; AC, adenylate cyclase; AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB, cannabinoid; DAGs, diacylglycerols; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; FABP, fatty acid-binding protein; MAGL, monoacylglycerol lipase; NAE, N-acylethanolamines; NAPE, N-acylphosphatidylethanolamine; NAPE-PLD, NAPE-specific phospholipase D.

Figure 3

Interaction between endocannabinoids, TRPV1, and CB1. Endocannabinoids can: (1) directly activate TRPV1 leading to cannabinoid receptor 1 (CB1)-independent effects; (2) activate CB1 leading to activation of the phospholipase C pathway enhancing TRPV1 activity; (3) activate CB1 leading to inhibition of the adenylate cyclase pathway inhibiting TRPV1 activity; (4) activate CB1 leading to TRPV1-independent effects.

Figure 4

Browning of WAT by TRPV1 activation. Activation of TRPV1 results in Ca²⁺ influx and the subsequent activation of CaMKII. CaMKII facilitates the subsequent activation of AMPK and SIRT1 allowing the deacetylation of PRDM16 and PPARγ allowing their interaction and promotion of WAT browning.

Figure 5

TRPV1 mediated activation of thermogenic activity in BAT. The calcium influx activates CaMKII leading to the eventual activation of SIRT1 and deacetylation of PRDM16 and PPARγ. SIRT1 also activates PGC-1α leading to the activation of PPARα. PGC-1α and PPARα transcriptionally activate UCP-1. TRPV1 also activates BMP8b which, along with UCP-1, PRDM, and PPARγ, cause increased thermogenic activity.