4.2 TRPA1 in BAT thermogenesis and modulation
Adaptive thermogenesis, refers to as the generation of heat in the body in response to external environmental stimuli has emerged as a potential option to counteract obesity. Brown adipose tissue (BAT) plays an essential role in the prevention of obesity due to a prominent role in the adaptive thermogenesis(Loh, Kingwell et al., 2017). BAT is characterized by the presence of uncoupling protein 1 (UCP1) and high mitochondrial content. UCP1, expressed in the inner membrane of BAT mitochondria, functions by uncoupling oxidative phosphorylation to generate heat and induction of thermogenesis(Fernández-Verdejo, Marlatt et al., 2019). Therefore, targeting BAT thermogenesis presents a suitable approach to enhance energy expenditure.
Adrenaline secretion from the adrenal gland has been linked to energy metabolism. It has been reported that capsaicin, a TRPV1 agonist induces adrenaline secretion in rats and increases the energy expenditure(T. Watanabe, Sakurada et al., 2001). Co-expression of TRPA1 with TRPV1 on the sensory neurons opens up the possibility of involvement of TRPA1 in elevating energy expenditure via adrenaline secretion. Iwasakiet al. in 2008 found that intravenous administration of AITC and cinnamaldehyde induce adrenaline secretion from the adrenaline gland in the anesthetized rats. They also showed that pre-treatment with the capsaicin diminishes the response in rats as capsaicin impairs the nerve functions(Iwasaki et al.. 2008). More energy consumption and thermogenesis due to adrenaline secretion could be due to the activation of the adrenergic receptor in BAT and upregulation of UCP1 protein in BAT tissue.
Similarly, a phenolic compound found in extra virgin olive oil; oleuropein aglycone reduces the total body weight, circulating plasma leptin and increases whole body thermogenesis by increasing the expression of UCP1(uncoupling protein) in BAT. Oleuropein activates both hTRPA1 and hTRPV1 expressed in HEK293 cells, with almost 10 times stronger potency for hTRPA1 over TRPV1. Consumption of oleuropein in high fat diet (HFD) fed rats reduces visceral fat through the activation of TRPA1 and TRPV1 followed by noradrenaline secretion via the β-2 and β-3 adrenoreceptors(Oi-Kano et al.. 2017).
Cinnamaldehyde is a pungent compound found in cinnamon, known to have many beneficial effects on metabolism, to check whether cinnamaldehyde intake could reduce fat accumulation, a study was conducted by Tamuraet al . in 2012 on high fat and high sucrose (HFS) diet fed mice. Visceral fat accumulation (WAT accumulation) was found to be lower in HFS fed mice when cinnamaldehyde was added to the HFS diet(Tamura et al. 2012). A clinical trial conducted by Michlig et al . also provide evidence that a single dose of cinnamaldehyde (70mg/200ml; 300ppm) significantly increases the energy expenditure by a magnitude of 3.6 kcal over the period of experiment as compared to the placebo group(Michlig et al. 2016). Recent evidences also suggested the possible mechanism for the anti-obesity effects of cinnamaldehyde (Camacho et al., 2015; Neto, Boechat et al., 2020). Subcutaneous fat depots contain thermogenic adipocytes which play an important role in thermoregulation and metabolic health during cold exposure. Chronic treatment with cinnamaldehyde stimulated the thermogenesis in adipocytes viaPKA/p38 MAPK dependent pathways(Jiang et al. 2017). In another report, it has been found that cinnamaldehyde administration to the HFD fed C57 mice leads to the browning of white adipose tissue. Upregulation of browning marker ucp1 along with higher expression of transcriptional factors like PPAR-γ (peroxisome proliferator-activated receptor gamma), PRDM16 (PRD1-BF-1-RIZ1 homologous domain containing protein-16) and PGC-1α (peroxisome proliferator-activated receptor gamma co-activator 1 α), leading to the browning of WAT has been reported along with anti-obesity effects of cinnamaldehyde(Zuo et al., 2017).
Royal jelly activates TRPA1 and TRPV1, stimulates energy expenditure and metabolism(Terada et al., 2011). In 2012, a human trial was conducted to evaluate the effect of royal jelly on body weight and dietary intake in diabetic patients. In the human trial, royal jelly supplementation resulted in a significant reduction in mean body weight (Pourmoradian et al.. 2012). In another set of experiment on HFD mice, royal jelly supplementation also reduced mean body weight, hepatic triglyceride content and stimulated BAT thermogenesis by increasing the expression of UCP1 protein in HFD fed mice. The possible mechanism for the body weight reduction is the activation of TRPA1 and thereby more thermogenesis and energy expenditure (Yoneshiro et al.. 2018).
Garlic is known for its beneficial properties for centuries. Garlic oil produced through steam distillation of raw garlic contains many sulfide compounds including diallyl disulfide (DADS), diallyl trisulfides (DATS), allyl sulfides, DAS (diallyl sulfides) and methyl allyl trisulfides (MATS). All these sulfide compounds which contribute to the goodness of garlic, are agonist of TRPA1 and TRPV1, where DATS (EC50 0.49µmol/l) was reportedly found to be a more potent agonist of TRPA1 than AITC(EC501.47µmol/l)(Koizumi et al., 2009). Garlic oil consumption to the high fat diet fed rats reduces the overall weight and white adipose tissue (WAT) mass (significant reduction was found in epididymal and subcutaneous WAT) as compared to the control group. Surprisingly there was no difference in the energy intake but a variation in energy efficiency was observed. It was reported that garlic oil administration lead to more O2 consumption and fat oxidation in HFD fed rats. UCP1 protein, responsible for non-shivering thermogenesis was also upregulated in BAT after garlic oil consumption(Kagawa et al.. 2019). Allicin, a bioactive sulfide present in garlic also activate TRPA1 channel. Recently, it has been demonstrated that allicin administration to the HFD fed and Db/Db mice significantly increased BAT activity and energy expenditure. In-vitro experiments performed on isolated brown adipose tissues from mice showed that allicin directly activates BAT by upregulating the expression of UCP1 protein(C. Zhang et al., 2020). Cumulatively, these studies suggested the direct effect of TRPA1 agonists for the prevention of obesity by enhancing energy expenditure.
Stimulation of BAT activity provides an alternative to deal with the obesity. A clinical trial conducted by Matsushita et al ., showed that a single dose of Kaempferia extract increases the energy expenditure by the activation of BAT in healthy individuals. The probable mechanism for higher activity was supposed to be mediated through TRP channels like TRPV1 and TRPA1 as this extract contains various flavonoids but due to lack of vanilloid compounds in the extract, TRPA1 turn out to be the potential reason for this effect(Matsushita et al. 2015).
3T3-L1 cells are regularly used for studying adipogenesis related markers and targets. trans -pellitorine, an alkamide found in piper and macro-piper species has activation potential for both TRPV1 and TRPA1. Treatment of 3T3-L1 cells with trans-pellitorine reduced lipid accumulation. Furthermore, TRPA1 has been reported to play an essential role during early to intermediate stages of maturation of pre-adipocytes by reducing the expression of PPAR-γ and fatty acid synthase (FAS) enzyme in 3T3 cells when treated with trans pellitorine(Lieder et al. 2017). This data suggested the involvement of TRPA1 in lipid accumulation in adipocytes, however, in-vivostudies are required to confirm the same.