4.3 TRPA1 and secretion of Gut hormones
Energy expenditure is also regulated by gut hormones including ghrelin, cholecystokinin (CCK) glucagon-like peptide (GLP-1) and peptide YY (PYY). These hormones are either secreted in a state of hunger (ghrelin) or post-prandially (CCK, GLP-1 and PYY)(Murphy & Bloom, 2006). STC-1 cell line is a neuroendocrine cell line that provides a betterin-vitro model to study the secretion pattern of both CCK and GLP-1 and to a lesser extent PYY(Purhonen, Louhivuori et al., 2008). STC-1 cells also express TRPA1 and treatment with AITC stimulated the secretion of satiety hormone CCK (Purhonen et al.. 2008). CCK is known for its role in regulating gastric motility, satiety, gastric emptying rate and appetite(Lean & Malkova, 2016). TRPA1 activation increases the intracellular calcium via calcium influx and it has been reported that calcium influx plays an important role in the secretion of CCKin-vivo . TRPA1 on the cell membrane when activated by agonists like AITC increases the influx of extracellular calcium into the cell which was blocked by the treatment with TRPA1 blockers. Their study demonstrated that calcium influx through activation of TRPA1 is required for the release of CCK from the STC-1 cell(Purhonen et al. 2008). Another group of scientists reported that di-unsaturated and mono unsaturated aldehydes activate TRPA1 to stimulate the secretion of CCK from STC-1 cells. There was reduced CCK secretion in the presence of TRPA1 antagonists and in the absence of extracellular calcium. Aldehydes were more potent than fatty acid and alcohol in terms of stimulation of CCK secretion in STC-1 cells(Nakajima et al.. 2014). Naringenin, a flavonoid found in citrus fruits also stimulates CCK release from STC-1 cells through TRPA1 mediated calcium signaling which was abolished in the presence of TRPA1 antagonists(Park et al. 2014). Similar reports have been published for the aglycone hesperidin and hesperetin found in oranges, stimulates CCK release from STC-1 cells via activation of TRPA1 channel and calcium influx mediated by TRPA1(H. Y. Kim et al. 2013). Poly-unsaturated fatty acids (PUFA) are obligatory in the mammalian diet and have many essential physiological functions inside the body. Since, TRPA1 can sense PUFA, this property of TRPA1 has opens up a new direction for its role in nutrient sensing in the intestine. Activation of TRPA1 by PUFA also stimulates the secretion of CCK (Motter & Ahern, 2012).
Cinnamon is used in traditional medicines for hundreds of years to treat post-prandial glycemia(Khan et al.. 2003; Solomon and Blannin 2009). The major anti-obesity effect of TRPA1 agonist cinnamaldehyde was found to be reduction in the ghrelin secretion in the HFD fed obese mice when given cinnamaldehyde containing diet for five weeks. Camacho et al. found that TRPA1 and ghrelin secreting cells co-localizes in the duodenum and they showed that cinnamaldehyde treatment upregulates the expression of TRPA1 in the MGN cell line(Camacho et al. 2015). Furthermore, cinnamaldehyde administration in HFD fed mice reduced fasting-induced hyperphagia, prevented weight gain and HFD induced inflammation(Khare et al., 2016). Even though cinnamaldehyde activates TRPA1, but these anti-obesity effects were not attributed to the direct involvement of TRPA1.
6-gingerol, the main active and pungent constituent of ginger, was used by Yang et al. to decipher the mechanism related with its beneficial effects in digestion. Using RIN14B and STC-1 cell lines, they showed that 6-gingerol activates TRPA1 in-vitro conditions and stimulates the release of 5-HT and CCK from RIN14B and STC-1 cells respectively. The use of TRPA1 specific antagonists abolishes the secretion of these hormones. They also provide the evidence for the significance of TRPA1 mediated calcium influx in the secretion of hormones from the endocrine cells of the gut(YANG et al. 2016).
Anorectic and orexigenic hormones secreted either from the brain or gastrointestinal tract regulate appetite and total dietary intake. Vomitoxin or deoxynivalenol (DON) is a mycotoxin that has been reported to suppress the food intake in mice models through the activation of TRPA1 and calcium sensing receptor (CaSR) (W. Wu et al. 2017). In earlier experiments, the same group of scientists showed that vomitoxin has anorectic effect in-vitro conditions as a short-term treatment of vomitoxin in STC-1 cells stimulates the secretion of GLP-1 and CCK via activation of CaSR and TRPA1 mediated calcium influx(Zhou & Pestka, 2015). Further to validate the same, they used mice models and found that both TRPA1 and CaSR are activated by vomitoxin, stimulated secretion of satiety hormones CCK and PYY. Also, anorectic effects of vomitoxin were abolished in the presence of TRPA1 and CaSR specific antagonists(W. Wu, Zhou et al., 2017). In addition,in-vivo results from another study reported increased gene expression of TRPA1 and CCK in the small intestine after 3 hours of vomitoxin administration, suggesting the anorectic effects of vomitoxin due to upregulation of CCK via TRPA1 (Tominaga et al. 2016).
Kim et al . demonstrated that methyl syringate, a pungent ingredient of Kalopanax pictus, is an electrophilic activator of the TRPA1 channel. They showed that through the activation of TRPA1, methyl syringate and cinnamaldehyde stimulated the secretion of PYY but not GLP-1 in ICR mice(M. J. Kim et al. 2013). TRPA1 activation potentially stimulates gut hormone secretion (Table 2). Chronic consumption of HFD downregulated the TRPA1 expression in the stomach, duodenum and ileum in mice. Reduced TRPA1 expression in HFD condition could be related with the diet induced complications like dysregulation in the secretion of gut hormones. It has been recently revealed that TRPA1 activation with allicin rich garlic extract prevented misbalance in the release pattern of the gut hormones (GLP-1, CCK, PYY and ghrelin) [unpublished data].
Hormone secretion in response to nutrients plays an important role in managing weight gain and obesity(Valassi, Scacchi et al., 2008). Being an activator of many food ingredients TRPA1 provides many advantages to be used as a therapeutic target to manage obesity and related complications.
In contrast, there are reports which stated that TRPA1 activation could lead to a stimulating effect on food intake. β-eudesmol is found in medicinal plants and activates human TRPA1 at an effective concentration (EC) of 32.5 ± 0.38μM. Oral administration of β-eudesmol to the rats increased serum ghrelin level and feed intake. But surprisingly there was no significant increase in the body weight of the rats. Ohara et al. also demonstrated the involvement of gastric vagal nerve activity (GVNA) in the appetite stimulant. GVNA level was found to be enhanced after the β-eudesmol administration that was significantly reduced when TRPA1 antagonist HC-03001 was given prior to the β-eudesmol (Ohara et al.. 2017).
TRPA1 and Diabetes
T2DM and obesity are positively correlated with each other in terms of its prevalence and occurrence(Kahn, Hull et al., 2006). It has been observed that weight gain is a major cause in the development of T2DM in approximately 90% of the cases. In individuals with obesity, insulin resistance in liver, WAT, skeletal muscle and insulin deficiency contribute to the development of T2DM. It is generally seen that serum levels of free fatty acids (FFA) remain elevated in people with obesity both at basal level and following glucose load. These circulating FFAs are the products of excess dietary lipids and lipolysis in adipose tissues. FFAs are the key factor in the development of insulin resistance. Increased plasma FFAs by the mass action augment their cellular uptake and induction of mitochondrial β-oxidation, at the same time interfering with the enzymatic regulation of the glucose homeostasis(Boden, 2011; Roden et al., 1996; Saini, 2010). More utilization of lipids results in the accumulation of glucose or a condition known as hyperglycemia which further leads to insulin resistance. Obesity causes hypertrophy as well as hyperplasia in WAT accompanied by changes in its adipokine profile including pro-inflammatory cytokines(Esser, Legrand-Poels et al., 2014; Heilbronn & Campbell, 2008). Excessive dietary lipids get stored around the liver, skeletal muscle and pancreatic β-cells due to obesity driven dysfunctional WAT. All these factors simultaneously increase the risk for developing T2DM. Despite available treatments, use of natural compounds regulating glucose homeostasis and/or preventing obesity induced insulin resistance offers a huge advantage. During the last decade, TRPA1 is extensively explored for its role in insulin secretion and GLP-1 secretion. Hence, modulating TRPA1 could be used as a target to combat diet induced insulin resistance and related complications. In this section, we have summarized recent evidences of TRPA1 being employed as a therapeutic target to control T2DM.