These results are consistent with the concept that increasing intracellular LC-CoA levels leads to enhanced Ca2+ influx through TRPV1 channels. The potential significance of our findings to health and disease still remains to be comprehensively determined in future studies. However, it is important to speculate how this LC-Acyl CoA/ TRPV1 axis might contribute to both cellular function and dysfunction. Any alterations in Ca2+ signalling due to increased TRPV1 channel function could result in detrimental effects on a variety of cellular processes. For example, TRPV1 channel activation is thought to result in the secretion of substance P and calcitonin gene-related peptide that exert pro-inflammatory effects. Application of capsaicin concentrations that desensitize TRPV1 channels result in a decrease in pain and levels of these inflammatory peptides. TRPV1 antagonists are currently being developed to address a wide variety of diseases. Interestingly, low-grade inflammation is now thought to be a central component in the development of T2D diabetes, a disease in which fatty acid metabolism is perturbed. TRPV1 is also suggested to play a direct role in immune/inflammatory cell activation as TRPV1 channels are expressed in macrophages, dendritic cells and T-cells resulting in an increase in the levels of pro-inflammatory mediators including IL-1b, IL-6, IL-12 and TNF-a. Therefore any mechanism that leads to excessive TRPV1 channel activity may play a role in immune/inflammatory disorders. Given the potentially important role that inflammation plays in the etiology of obesity and metabolic disorders, excessive TRPV1 activity may be involved. Indeed, exposure of rodents to capsaicin-containing diet resulted in a leaner phenotype. In addition, WT mice fed a high fat diet weeks gained significantly more weight than TRPV1 knockout mice. TRPV1 knockout mice on a HFD also showed improved glucose tolerance compared to WT mice on a HFD. Collectively these findings suggest that excessive TRPV1 activation may be a contributing mechanism to the development of obesity and T2D. It is tempting to speculate that increased LC-CoA-mediated TRPV1 channel activation may occur via changes in fatty acid metabolism and transport observed in T2D and obesity where dietary consumption of saturated fatty acids is a contributory factor. In summary, our study reports a novel mechanism by which physiological concentrations of intracellular LC-CoA potently modulate TRPV1 channel via a mechanism similar, but not identical to PIP2. As many TRP family members are regulated by PIP2, our results reveal a metabolically-linked mechanism by which TRP channels activity may be regulated. This mechanism may contribute to the cellular dysfunction observed in immune/ inflammatory cell types in certain metabolic disorders that display altered fatty metabolism such as T2D and obesity. Further studies to test this concept are therefore warranted.