The role of adipose TRP channels in the pathogenesis of obesity

Abstract

The prevalence of obesity is continuously increasing worldwide. Transient receptor potential (TRP) channels constitute a family of nonselective cation channels that are ubiquitously expressed in mammalian tissues, including adipose tissue. Although TRP channels might be regarded as therapeutic targets for obesity due to the inhibitory effects of their agonists on body weight and adiposity, the exact role of TRP channels in the development of obesity by modulating the function of adipose tissue has not been systemically reviewed. Multiple TRP channels are present in adipocytes and are involved in diverse aspects of cellular function, including differentiation and maturation of white adipose tissue (WAT), browning of WAT and thermogenesis of brown adipose tissue (BAT). Most of these functions are mediated by alterations in intracellular Ca²⁺ levels or subcellular Ca²⁺ signaling pathway. TRP channels influence intracellular Ca²⁺ dynamics through directly mediating Ca²⁺ entry (TRPVs and others) or store‐operated mechanisms (TRPCs). Intracellular Ca²⁺ displays a biphasic effect on regulation adipocyte behaviors depending on the differentiation stage, which may account for the different roles of individual TRP channels in regulation of adiposity. This review emphasizes the contribution of TRP channels to obesity and provide an in‐depth discussion on the complexity of their mechanism of actions.

This review emphasizes the contribution of transient receptor potential (TRP) channels to obesity through regulating the differentiation process and function of adipocytes. TRP channels influence intracellular Ca²⁺ dynamics through directly mediating Ca²⁺ entry (TRPVs and others) or store‐operated mechanisms (TRPCs). The fact that intracellular Ca²⁺ displays a biphasic effect on regulation adipocyte behaviors may account for the different roles of individual TRP channels in regulation of adiposity.

1. INTRODUCTION

Obesity has long been considered as one of the greatest public health issues worldwide. Epidemiologic studies have identified that the prevalence of obesity has continuously increased in most countries worldwide and has reached two‐fold in no less than 70 countries (Afshin et al., 2017). In addition, obesity also facilitates or promotes the development of many obesity‐associated diseases, including heart disease, dyslipidemia, insulin resistance, Type 2 diabetes, hypertension, and many types of cancer (Bornfeldt & Tabas, 2011; Lloyd‐Jones et al., 2009). It is widely accepted that reducing the number of calories consumed and increasing energy expenditure (EE) could prevent or even treat obesity, which is usually recommended in clinical practicing. However, sustained change in dietary habit or physical activity requires an enormous willpower, which is rather difficult to achieve in our daily life. Compared with self‐modification weight loss techniques such as diet and exercise, patients with obesity are more satisfied with pharmacotherapy/surgical approaches (Gupta & Wang, 2016). But, pharmaceutical drugs, such as orlistat, display a variable efficacy and some side effects, like gastrointestinal adverse effects, acute kidney injury, and liver failure (Filippatos et al., 2008). In addition, although metabolic surgery such as sleeve gastrectomy or Roux‐en‐Y gastric bypass displays potent antiobesity effect, it could not be accepted by every patient for it is invasive, too expensive, accompanied by an uncertain long‐term effect (Hanipah & Schauer, 2017). Alternatively, some active natural ingredients from food, especially the condiments, such as capsaicin, cinnamaldehyde and menthol, have been received much attention to be an effective antiobesity lifestyle intervention approach for their safety, availability and convenience (M. Saito, Yoneshiro, & Matsushita, 2015). We and others have reviewed the antiobesity effects of capsaicin (Zheng, Zheng, Feng, Zhang, & Xiao, 2017) and its protective role in metabolic disorders (F. Sun, Xiong, & Zhu, 2016). The common characteristics of these components is that they all serve as activators of the transient receptor potential (TRP) channels.

The TRP channel family includes 27 related members that respond to different types of chemical (both endogenous and exogenous) and physical (voltage, temperature, force, pressure, and tension) stimuli (Jara‐Oseguera & Islas, 2013; Nieto‐Posadas, Jara‐Oseguera, & Rosenbaum, 2011). They are usually found localizing on the plasma membrane and exert their functions as nonselective cation channels. There exist six TRP subfamilies: “vanilloid” TRPVs (TRPV1–6), “canonical” TRPCs (TRPC1–7), “polycystin” TRPPs (TRPP2, TRPP3, TRPP5), “melastatin‐like” TRPMs (TRPM1–8), “mucolipin” TRPMLs (TRPML1–3), and a single member “ankyrin‐rich” TRPA (TRPA1). The conserved structure of all these TRP channels contain a six transmembrane domains and a cation‐permeable pore region between Segment 5 and 6, and the highly variable intracellular N‐ and C‐termini of these molecules contribute to the functional difference of TRP members (Owsianik, D'Hoedt, Voets, & Nilius, 2006). TRP channels are ubiquitously expressed and they display different functions depending on the specific tissue type. Ever since we first discovered the existence of TRPV1 mRNA and protein in adipose tissue and 3T3‐L1 preadipocytes (L. L. Zhang et al., 2007), there exist many reports on TRP channel function in adipocyte biology. Bishnoi, Kiran kondepudi, Gupta, Karmase, and Boparai (2013) selected 12 TRP channel subtypes to detect their mRNA expression in mouse adipose tissue and 3T3‐L1 preadipocytes. They found a relatively higher expression of TRPV2/4, TRPC1, TRPP2 (PKD2), and TRPM2 channels in mature adipocytes while TRPV1, TRPV3, TRPM8, TRPC4, and TRPC6 displayed significantly higher expression level in preadipocytes as compared to adipocytes (Bishnoi et al., 2013), indicating that TRP channels participate and exert different roles in the differentiation of adipocytes. We have previously reviewed the distribution and individual function of TRP members in metabolic tissues, including liver, pancreas, adipose tissue, skeletal muscle, and so on (Zhu, Luo, Ma, & Liu, 2011). However, the exact role of TRP channels in the pathogenesis and progression of obesity by modulating the function of adipose tissue has not been systemically reviewed.

There are two main types of adipose tissues with different origins in the body, brown adipose tissue (BAT) and white adipose tissue (WAT). It is generally believed that myogenic factor 5‐positive (Myf5⁺) adipose progenitor cells derived from skeletal muscle cell line precursors, differentiate into brown adipocytes, while another population of Myf5^‐ cells differentiate into white adipocytes (Harms & Seale, 2013). WAT represents the main energy reservoir of the body, it can be divided into visceral (around organs – mesenteric, perigonadal, omental) and subcutaneous (under the skin – inguinal) depots, with some metabolic and endocrine differences between them. White adipocytes usually contain a large lipid drop that squeezes the nucleus around the cell edge, containing a small number of mitochondria. Hyperplasia and hypertrophy of white adipocytes are the main feature of obesity. Compared with WAT, the distribution of BAT is more specific, mainly located in cervical, supraclavicular, paravertebral, mediastinal, and perirenal regions in humans (Park, Kim, & Bae, 2014). Brown adipocytes in BAT contain several small lipid droplets, a central nucleus and large amounts of mitochondria that contain uncoupling protein‐1 (UCP1). BAT is a key site of UCP1‐mediated heat production in mammals thus it has been considered an attractive target to promote weight loss. In addition, there also exist some adipocytes in WAT resemble the brown adipocytes phenotype after permanent thermogenic induction, such as cold and activation of β‐3 adrenergic receptor, called “beige” or “brite” adipocytes (Harms & Seale, 2013). Compared with visceral adipocytes, subcutaneous adipocytes are more prone to differentiate into beige adipocytes because they are predominantly smaller and have a greater potential to differentiate. Therefore, using beige adipocytes and browning of WAT to counteract obesity has gained much more attention than BAT, as the actual amount of BAT in human body is quite low and displays a negative relationship with body mass index (BMI) or age (Bartelt & Heeren, 2014). Recent studies have shown that TRP channels function as a key factor in regulating ion homeostasis in adipocytes and play an important role in the development and differentiation of adipose tissue. Therefore, the role of TRP channels in regulating the morphology and function of adipose tissue and its underlying molecular mechanism are reviewed in this paper.

2. MODULATION OF CYTOSOLIC Ca ²⁺ LEVEL IN ADIPOSE TISSUE BY TRP CHANNELS

Almost all TRP channels are located at the plasma membrane and permeable to Ca²⁺ (Table 1). They function as regulators of intracellular Ca²⁺ level and several have a strong influence on Ca²⁺‐dependent signaling pathways by mediating direct Ca²⁺ influx, receptor‐operated Ca²⁺ influx, or store‐operated Ca²⁺ influx (Earley & Brayden, 2015). As a second messenger, appropriate intracellular Ca²⁺ level maintains normal differentiation and physiological function of adipocytes, while the imbalance of Ca²⁺ results in abnormal adipocyte function, excessive fat deposition, and obesity (Arruda & Hotamisligil, 2015). In vitro studies indicated that increasing intracellular Ca²⁺ level inhibited adipocyte differentiation at the early stage, but promoted differentiation at the later stage, displaying a biphasic effect (Ntambi & Takova, 1996; Shi, Halvorsen, Ellis, Wilkison, & Zemel, 2000). Similarly, an acute rise in cytosolic Ca²⁺ stimulated lipolysis, which could be inhibited by sustained high levels of Ca²⁺ (Zemel, Shi, Greer, Dirienzo, & Zemel, 2000). Increased deposition of Ca²⁺ also exists surrounding the lipid droplets in hypertrophic adipocytes, accompanied by increased cytosolic Ca²⁺ levels (Giordano et al., 2013). Ca²⁺/calmodulin‐dependent kinases (CaMK) and calcineurin are the two main Ca²⁺ sensors involved in signal transduction in the cytosol. Activated by Ca²⁺, CaMKs directly phosphorylate and activate many important targets, including the pro‐inflammatory signaling molecules JNK and p38, energy sensor AMP‐activated protein kinase (AMPK) and transcription factors including Forkhead box O (FoxO) and cAMP response element‐binding protein (CREB). Sustained high Ca²⁺ level also activates calcineurin to regulate the activity of NFAT, an important transcription factor driving the expression of inflammatory genes (Arruda & Hotamisligil, 2015). Therefore, TRP channels participate in many cellular behaviors of adipocytes by regulating intracellular Ca²⁺ level, including metabolism, differentiation, and gene expression regulation. In addition to TRP channels, the functions of other channels regulating the adipocyte ion level on obesity, including K⁺ channels and Ca²⁺ channels, have been reviewed elsewhere (Vasconcelos, Souza, Pinheiro, & Silva, 2016).

Table 1.

Characterization of TRPs in adipocytes

TRP channel	Adipose tissue distribution	Species	Cation preference (PCa/PNa)	Subcellular localization	Functions
TRPV1	3T3‐L1 preadipocytes (Bishnoi et al., 2013; L. L. Zhang et al., 2007)	Mice Human	∼10 (Caterina et al., 1997)	Plasma membrane (PM), ER, and Golgi compartments (Dong, Wang, & Xu, 2010)	Reduction of adipogenesis (L.L. Zhang et al., 2007)
					TRPV1‐null mice gained significantly less mass and adiposity than WT controls on HFD (Motter & Ahern, 2008)
	Visceral and subcutaneous adipose tissue (L. L. Zhang et al., 2007)
					TRPV1 KO mice consumed more food and developed leptin resistance and obesity after HFD (Lee et al., 2015)
	Epididymal fat, subcutaneous fat pads from the inguinal region and BAT (Baskaran et al., 2016; Baskaran et al., 2017)
					Browning of WAT and maintenance of BAT (Baskaran et al., 2016; Baskaran et al., 2017)
				Mitochondria (cardiomyocytes) (Lang et al., 2015)	Regulation of BAT clock gene oscillations (Moraes, Mezzalira, et al., 2017)
TRPV2	3T3‐L1 adipocytes (Bishnoi et al., 2013)	Mice	1–3 (Kanzaki et al., 1999)	PM and early endosome (Dong et al., 2010)	TRPV2 KO mice possess more WAT and dysfunctional BAT, with HFD‐induced obesity (W. Sun, K. Uchida, Y. Suzuki, et al., 2016).
	Cultured brown adipocytes and BAT (W. Sun, K. Uchida, Y. Suzuki, et al., 2016).
					TRPV2 activation negatively regulated their brown adipocytes differentiation (W. Sun, K. Uchida, N. Takahashi, et al., 2016).
				ER (Nagasawa et al., 2007)
TRPV3	3T3‐L1 preadipocytes (Bishnoi et al., 2013)	Mice	12 (H. Xu et al., 2002)	PM (Dong et al., 2010)	TRPV3 activators prevented adipogenesis and weight gain in the mice fed on HFD (Cheung et al., 2015).
	iBAT and sWAT (W. Sun et al., 2017)
TRPV4	3T3‐L1 adipocytes (Bishnoi et al., 2013)	Mice	6 (Strotmann, Schultz, & Plant, 2003)	PM (Dong et al., 2010)	Inhibition or knockout of TRPV4 promoted browning of WAT, reduced adipose inflammation and protected mice from diet‐induced obesity and insulin resistance (Ye et al., 2012).
	WAT and BAT (Ye et al., 2012)
TRPC1/5	3T3‐L1 adipocytes (Bishnoi et al., 2013)	Mice Human	C1:Nonselective; C5: 9 (Owsianik, Talavera, et al., 2006);	PM (Dong et al., 2010)	Channels inhibiting the adiponectin production (Sukumar et al., 2012)
	Perivascular adipose tissue (Sukumar et al., 2012)
					Knockout of TRPC1 protects against high fat‐induced obesity (Krout et al., 2017).
TRPP3		Mice	4 (Owsianik, Talavera, et al., 2006)	PM (Dong et al., 2010)	TRPP3 facilitates BAT differentiation by enhancing mitochondrial function (Goralczyk et al., 2017)
TRPM2	3T3‐L1 adipocytes (Bishnoi et al., 2013)	Mice	0.5–1.6 (Owsianik, Talavera, et al., 2006)	PM and LEL compartment (Dong et al., 2010)	TRPM2‐KO mice were more insulin sensitive and resistant to diet‐induced obesity and inflammation (Zhang et al., 2012)
	WAT (Sun et al., 2017; Zhang et al., 2012)
TRPM7	3T3‐L1 preadipocytes and human adipocytes (Che et al., 2014; K. M. Chen et al., 2014).	Mice Human	3 (Owsianik, Talavera, et al., 2006)	PM and synaptic vesicles (Dong et al., 2010)	Silencing TRPM7 reduced proliferation and decreased adipogenic differentiation of preadipocytes (Che et al., 2014; K.H. Chen et al., 2014).
TRPM8	3T3‐L1 preadipocytes (Bishnoi et al., 2013)	Mice Human	1–3 (Owsianik, Talavera, et al., 2006)	PM and ER (Dong et al., 2010)	Activation of TRPM8 mediates BAT thermogenesis (S. Ma et al., 2012)
	BAT (S. Ma et al., 2012)
					Promoting browning of WAT (Rossato et al., 2014)
	WAT (Rossato et al., 2014)
					Regulation of clock and clock‐controlled genes in BAT (Moraes, de Assis, et al., 2017).

ER: endoplasmic reticulum; TRP: transient receptor potential.

3. TRPVs AS IONOTROIPC Ca ²⁺ INFLUX CHANNELS AND REGULATORS OF ADIPOCYTE DIFFERENTIATION

3.1. TRPV1 and TRPV3

As the first identified TRPV member (Caterina et al., 1997), TRPV1 could be activated by many environmental factors such as heat higher than 43°C and some natural ingredients in chili peppers such as capsaicin. Our previous studies have showed that dietary capsaicin prevents obesity in rats (L. L. Zhang et al., 2007). We observed that capsaicin dose‐dependently increased intracellular calcium in 3T3‐L1‐preadipocytes to inhibit their differentiation. In mature adipocytes, the capsaicin‐activated calcium increase was significantly reduced due to TRPV1 downregulation during adipogenesis (L. L. Zhang et al., 2007). Recently, direct effects of adipose‐derived TRPV1 on regulation of adipose differentiation and obesity have received much attention. Accumulating evidence suggests that browning of WAT might represent a novel strategy to counteract obesity (Bartelt & Heeren, 2014). Three core regulators of browning of WAT are peroxisome proliferator‐activated receptor‐γ (PPARγ), PR domain containing 16 (PRDM16) and PPARγ coactivator 1α (PGC‐1α). As the central factor accounting for the differentiation and maintenance of BAT, PRDM16 is required and sufficient to promote browning of WAT (Seale et al., 2007; Seale et al., 2008). The induction of the browning gene program in subcutaneous WAT in mice by activation of PPARγ is required to the existence of PRDM16 (Ohno, Shinoda, Spiegelman, & Kajimura, 2012). Also, sirtuin‐1 (SIRT1)‐mediated deacetylation of PPARγ is a key step of the recruitment of PRDM16 to the PPARγ transcriptional complex, which facilitates browning of white adipocytes (Qiang et al., 2012). As a crucial modulator of mitochondrial biogenesis, PGC‐1α controls thermogenesis and respiration of BAT through induction of uncoupling proteins in mitochondria and regulation of some nuclear respiratory factors (Wu et al., 1999). Baskaran et al. reported that epididymal fat (EF), subcutaneous fat pads from the inguinal region (SCF) and BAT of mice expressed TRPV1 channel protein, which was repressed by high fat diet (HFD). They also observed that capsaicin increased intracellular Ca²⁺ level of adipocytes in a TRPV1‐dependent manner, thus phosphorylated SIRT1 by activating AMPK and facilitated the interaction of PPARγ and PRDM16 to promote browning of WAT (Baskaran, Krishnan, Ren, & Thyagarajan, 2016). In addition, activation of TRPV1 by capsaicin also displayed a similar effect in BAT that counteracts obesity by stimulating metabolism and EE (Baskaran et al., 2017). Similarly, another TRPV1 agonist, monoacylglycerol, also increases uncoupling protein 1 (UCP1) content in BAT and reduces visceral fat mass in mice on HFD (Iwasaki et al., 2011). Besides direct regulating its differentiation, TRPV1 also acts as a critical modulator of clock gene oscillations in BAT. In physiological conditions clock machinery controls thermogenesis through activation of UCP1 in BAT, and its disruption leads to obesity and metabolic syndrome in the absence of TRPV1 (Moraes, Mezzalira et al., 2017).

However, it is also reported that knockout of TRPV1 protects against diet‐induced obesity (Motter & Ahern, 2008). It is possibly because preadipocytes are sensitive to calcitonin gene‐related peptide (CGRP) and TRPV1 positive nerves are the major source of CGRP. In this way, TRPV1 could regulate adipocyte function by acting on the neurons surrounding adipose tissue. TRPV1 deletion also protects against obesity‐induced hypertension and inhibition of low‐grade inflammation, indicating that TRPV1 may play a critical role in the initiation and pathogenesis of the metabolic syndrome (Marshall et al., 2013). Consistently, some antagonists of TRPV1, such as N‐(4‐tertiarybutylphenyl)‐4‐(3‐chloropyridin‐2‐yl) tetrahydropyrazine‐1(2H)‐carbox‐amide (BCTC) and AZV1, were shown to improve insulin resistance in diabetic mice, which may be related to the inhibition of TRPV1 in adipocytes (Zsombok & Derbenev, 2016). However, others have also reported that lack of TRPV1 facilitates leptin resistance and further promotes obesity and insulin resistance, accompanied by an increased food intake and decreased physical activity, suggesting that TRPV1 plays a major role in regulating leptin signaling in hypothalamic region (Lee et al., 2015). These contradictory findings indicate the complexity of the beneficial effects of TRPV1 on obesity. As TRPV1 ligands (e.g., capsaicin) not only affect the adipose tissue, but also display potent influence on the pancreas, central nervous system, and even the gut microbial composition, the results from dietary intervention may not reflect the real function of TRPV1.

TRPV3 possesses a high noxious activation threshold > 50°C upon initial activation and it becomes responsive to warm temperatures, indicating that it can function as either a nociceptor or a warmth receptor (Liu & Qin, 2017). Similar to TRPV1, the expression of TRPV3 in both interscapular BAT and subcutaneous WAT was significantly decreased in HFD‐induced obese mice and db/db (leptin receptor deficient) mice, whereas the mRNA levels of TRPV2 and TRPV4 were increased (Sun et al., 2017). High‐fat diet feeding increased TRPV3 expression in the hypoglossal nucleus (HN) and medial nucleus tractus solitarius (mNTS) in rats, accompanied by a reduced expression of proopiomelanocortin (POMC), an anorectic agent, resulting in increased food intake and body‐weight gain (Hu, Choo, & Ma, 2011). Cheung et al. discovered that TRPV3 agonists, including (‐)‐epicatechin and diphenylborinic anhydride, prevented adipogenesis by inhibiting the phosphorylation of insulin receptor substrate 1 in 3T3‐L1 adipocytes. In vivo, the antiadipogenic role of TRPV3 was further determined by the fact that chronic treatment with the TRPV3 activators prevented adipogenesis and weight gain in the mice fed on high‐fat diets. The expression of TRPV3 was also reduced in the visceral adipose tissue from HFD‐treated, db/db, and ob/ob mice (Cheung, Huang, Kwan, Chung, & Yao, 2015). It is worth noting that TRPV3 gene is located immediately next to the gene for TRPV1 (separated by 7.45 kbs) and they are in the same transcriptional orientation (S. Saito, Fukuta, Shingai, & Tominaga, 2011). Moreover, TRPV1 and TRPV3 usually form functional heteromeric channels (W. Cheng et al., 2012). These evidence partially explain the similarity between TRPV1 and TRPV3 in their effects on obesity.

3.2. TRPV4 and TRPV2

TRPV4 is a broadly expressed, calcium‐permeable ion channel that was first identified as an osmolality sensor (Liedtke et al., 2000; Strotmann, Harteneck, Nunnenmacher, Schultz, & Plant, 2000), which could be activated by many physical and chemical stimuli, including heat, mechanical stress, anandamide, arachidonic acid, and its derivatives (Everaerts, Nilius, & Owsianik, 2010; Nilius, Owsianik, Voets, & Peters, 2007). In adipose tissue, TRPV4 is highly expressed (Liedtke et al., 2000), and its expression is higher in WAT than in BAT (Ye et al., 2012). A recent study found that maternal obesity causes an almost six‐fold increase in TRPV4 mRNA expression in offspring's WAT, which could be completely blunted by dietary intervention (Janoschek et al., 2016). A Taiwanese population‐based TRPV4 genotyping study also suggests that genotypes at the TRPV4 locus independently affect BMI and obesity status in subjects (Duan et al., 2015). TRPV4 acts as a major Ca²⁺ influx channel as the amount of Ca²⁺ entering through a single TRPV4 channel is estimated to be 100‐fold more than that of a single l‐type Ca²⁺ channel, enough to activate a variety of Ca²⁺‐dependent signaling cascades (Mercado et al., 2014). A study by Ye et al. (2012) determined that there existed functional TRPV4 in adipocytes as both hypotonicity and the TRPV4 agonist GSK1016790A induced a TRPV4‐dependent increase in intracellular calcium. Knockdown of TRPV4 resulted in robust increased mRNA expression levels of PGC‐1α and its thermogenic targets, UCP1 and other mitochondrial genes, thus promoted oxidative metabolism and respiration of adipocytes. In vivo, deletion or pharmacological inhibition of TRPV4 activated EE and brown fat function, decreased inflammation and protected mice from diet‐induced obesity and insulin resistance (Ye et al., 2012). Although they did not assess the direct role of TRPV4‐mediated Ca²⁺ influx in regulating PGC‐1α expression, inhibition of extracellular signal‐regulated kinase (ERK)1/2 by U0126 effectively blocked the promotional effect of TRPV4 on PGC‐1α expression, suggesting that inhibition of TRPV4 facilitates browning of white adipocytes by reducing the intracellular Ca²⁺ level (Ye et al., 2012). Consistently, another report has determined the protective role of TRPV4 knockout in antagonizing diet‐induced obesity and they observed an increased PGC‐1α expression level in skeletal muscle (Kusudo, Wang, Mizuno, Suzuki, & Yamashita, 2012). However, they also pointed out that the activity of Ca²⁺‐dependent phosphatase calcineurin was elevated in the skeletal muscle of TRPV4^−/− mice, accompanied by compensated overexpression of TRPC3 and TRPC6 (Kusudo et al., 2012). In contrast to TRPV4, TRPC6 has been reported to highly expressed in BAT and its expression was reduced during adipocyte maturation, and TRPC3 was not detected in adipocytes (Bishnoi et al., 2013). Based on the fact that Ca²⁺ exerts biphasic effects on adipocyte differentiation depending on the early or late stage (Ntambi & Takova, 1996; Shi et al., 2000), it could be deduced that TRPV4‐mediated Ca²⁺ influx would be more prone to promote adipocyte maturation. Noticeably, calcium signals evoked by the TRPV4 agonist GSK1016790A were much more consistent than other tested TRP channels as reported (Mulier, Vriens, & Voets, 2017), which might explain why the function of TRPV4 seems not identical with most other TRP channels. However, a contradictory study also report that knockout of TRPV4 increased weight gain and adiposity under HFD (O'Conor, Griffin, Liedtke, & Guilak, 2013). Due to the lack of data on in vivo adipocyte Ca²⁺ level in Ye's study, the direct role of TRPV4‐dependent Ca²⁺ influx in regulating adipocyte differentiation still needs further confirmation.

Similar to TRPV4, the expression level of TRPV2 is also significantly increased in differentiated adipocytes compared to pre‐adipocytes (Sun, Uchida, Takahashi et al., 2016). TRPV2 is activated by noxious heat higher than 52°C (Caterina, Rosen, Tominaga, Brake, & Julius, 1999) and by some chemical ligands, including 2‐aminoethoxydiphenyl borate (2APB), lysophosphatidylcholine (LPC) and SKF96365 (SKF) (Juvin, Penna, Chemin, Lin, & Rassendren, 2007; Monet et al., 2009; Ramsey, Delling, & Clapham, 2006). Several studies by Sun et al. have revealed an important role of TRPV2 in the thermogenesis and differentiation of BAT. They observed the mRNA levels of thermogenic genes, such as UCP1 and PGC‐1α, were significantly lowered in both cultured brown adipocytes and BAT from TRPV2 knockout (TRPV2^‐/‐) mice. TRPV2^‐/‐ mice have more WAT and accumulation of dysfunctional BAT, accompanied by an increased body weight and fat upon high‐fat‐diet treatment (Sun, Uchida, Suzuki et al., 2016). In addition, TRPV2‐mediated calcium influx was also required for BAT activation‐induced thermogenesis and brite phenotype (Sun, Uchida, Suzuki et al., 2016). These findings indicate that TRPV2 is indispensable to promote differentiation and maintenance of functional BAT in vivo. However, they also observed that TRPV2 activation negatively regulated the differentiation of brown adipocytes at an early differentiation stage by increasing intracellular Ca²⁺ level. The calcineurin inhibitors cyclosporine A and FK506 partially recovered TRPV2 activation‐induced inhibition of brown adipocyte differentiation (Sun, Uchida, Takahashi et al., 2016), indicating that increased Ca²⁺ influx hampered brown adipocyte differentiation via calcineurin‐dependent signaling pathway. Therefore, it could be assumed that excess Ca²⁺ influx displays a detrimental effect on the differentiation of BAT, whereas a relative higher intracellular Ca²⁺ level is required to maintain a normal thermogenesis function of BAT, that would be the reason why the expression of TRPV2 increased during the maturation of BAT.

Cation permeability is an important factor influencing the substantial biological behaviors. The monovalent cations Na⁺ and K⁺ act as important regulators of cellular membrane potential and excitability, whereas the divalent cations Ca²⁺ and Mg²⁺ function as intracellular second messengers or cofactors for enzymatic activity. These cations also affect obesity by regulation of adipocyte proliferation, central or peripheral food intake, body EE or gastric emptying, and so on (Vasconcelos et al., 2016). As TRPV1/2/3/4 display a rather low discrimination between divalent and monovalent cations (P_Ca/P_Na between 1 and 10) (Benham, Davis, & Randall, 2002; Gunthorpe, Benham, Randall, & Davis, 2002; Voets & Nilius, 2003; Voets et al., 2002), the different effects of these four adipose TRPV channels might not depend on their preference for cations. Unlike TRPV1 or TRPV3, TRPV2, and TRPV4 with higher expression in mature adipocytes or WAT often display responsibility to hypo‐osmotic stress or cell swelling (Bishnoi et al., 2013; Plant, 2014). TRPV2 has been reported to localize mainly in intracellular pools under basal conditions and translocate from the cytosol to the plasma membrane by insulin‐like growth factor 1 (IGF‐1) stimulation (Kanzaki et al., 1999). This translocation is mediated by phosphoinositide 3‐kinase (PI3K) and G‐protein pathways (Nagasawa, Nakagawa, Tanaka, & Kojima, 2007). Importantly, a study on immune system has pointed out that TRPV2 is required for activation of the NLR family, pyrin domain‐containing 3 (NLRP3) inflammasome under cell swelling by activating TAK1, which could be blocked by TRPV2 inhibitor 2‐APB (Compan et al., 2012). Similarly, TRPV4 deficiency also reduced adipose inflammation (Ye et al., 2012). Therefore, it could be deduced that activation of adipose TRPV2 or TRPV4 in WAT might be a compensated response of organism to the increased volume of adipocytes in obese subjects, resulting in an increased inflammation in adipose tissue. However, as intracellular Ca²⁺ is required for the common respiratory activity of mitochondria, a much higher Ca²⁺ level is required for maintaining a normal thermogenesis process in BAT (Rizzuto, De Stefani, Raffaello, & Mammucari, 2012). That is to say, excessive Ca²⁺ influx might display opposite effects on WAT and BAT possibly due to the enormous difference of mitochondria content between them. Thus, the higher expression level of TRPV2 or TRPV4 would help to supply enough Ca²⁺ influx to stimulate thermogenesis in BAT, which could partially explain why knockout of TRPV2 in BAT promotes obesity whereas knockout of TRPV4 in WAT improves obesity (Figure 1).

Figure 1.

The effects of TRPV‐mediated Ca²⁺ influx in adipocytes. (a) The expression level of TRPV1 or TRPV3 is reduced during the differentiation of adipocytes, while that of TRPV2 or TRPV4 is increased in the process of maturation. (b) TRPV1 channels are expressed in both WAT and BAT, and activation of TRPV1 facilitates Ca²⁺ influx and promotes the binding of PPARγ and PRDM16 on the promoter of UCP1 via CaMKK/AMPK/SIRT1 signaling pathway, thus stimulates thermogenesis in BAT and browning of WAT. In WAT, TRPV4‐mediated Ca²⁺ influx displays an inhibitory effect on PGC‐1α by phosphorylation of ERK1/2, promoting adipose inflammation. (c) TRPV2 activation negatively regulated the differentiation of brown adipocytes, whereas TRPV2‐mediated calcium influx promotes differentiation and maintenance of functional BAT. BAT: brown adipose tissue; WAT: white adipose tissue [Color figure can be viewed at wileyonlinelibrary.com]

4. TRPCs AS STORE‐OPERATED CHANNELS AND MODULATORS OF ENDOPLASMIC RETICULUM STRESS IN ADIPOCYTES

Unlike many other ion channels, TRPCs are not voltage‐ or neurotransmitter‐gated but activated by relatively slow chemical and physical activators to stimulate intracellular Ca²⁺ signaling pathway. TRPC1 usually interacts with TRPC4 or TRPC5 to form a functional tetrameric complex and homomeric TRPC1 alone could not form a functional channel, because the localization of TRPC1 on the plasma membrane requires the existence of TRPC4 or TRPC5 (Myeong et al., 2016). These three members of TRPCs mainly fulfill the function as store‐operated Ca²⁺ entry (SOCE), by interact with or in parallel to the key players of SOCE, ORAI calcium release‐activated calcium modulator 1 (ORAI1), and stromal interacting molecule 1 (STIM1) (Eder, 2017). Recently, increased extracellular level of adenosine triphosphate (ATP), which might represent a high energy status, has also been reported to stimulate Ca²⁺ influx in adipocytes through ORAI1 and STIM1 (El Hachmane, Ermund, Brännmark, & Olofsson, 2018). SOCE through ORAI1 stimulates TRPC1 channels to translocate into the plasma membrane where they mediate a secondary Ca²⁺ influx event (K. T. Cheng, Liu, Ong, Swaim, & Ambudkar, 2011). Sukumar et al. have screened the expression of TRPCs in 3T3‐L1 adipocytes and determined that there were only TRPC1 and TRPC5 expressed, which was also confirmed in perivascular adipose tissue. They also observed a marked upregulation of TRPC1 and TRPC5 mRNAs as the cells differentiated in mature adipocytes. The arising Ca²⁺ influx through these channels inhibited the generation of adiponectin, an important adipokine beneficial to cardiovascular system, from adipose tissue, which could be rescued by dietary ω‐3 fatty acids (Sukumar et al., 2012). Consistently, a study by Krout et al. also confirmed the negative role of TRPC1 in HFD‐induced obesity. Knockout of TRPC1 protects against high fat‐induced obesity and elevation of fasting glucose level, accompanied by a decreased number of adipocytes in both subcutaneous and visceral adipose tissue, suggesting that TRPC1‐mediated Ca²⁺ entry blocks adipocyte cell death and promotes obesity (Krout et al., 2017). Acting as an adiposity regulator, changes in the SOCE‐dependent Ca²⁺ levels in adipocytes not only regulates the body fat content, but also enhances short neuropeptide F (sNPF) expression in the brain by a currently unrecognized non‐tissue‐autonomous manner (Baumbach et al., 2014). In addition, Bishnoi et al. reported that TRPC4 and TRPC6 were differentially expressed in pre‐adipocytes and adipocytes, suggesting that they may be also involved in adipogenesis (Bishnoi et al., 2013).

The endoplasmic reticulum (ER) is the crucial organelle accounting for synthesis, folding and maturation of secreted and transmembrane proteins, lipid biosynthesis, and serves as the most important Ca²⁺ store in the cell (Ron & Walter, 2007; van Meer, Voelker, & Feigenson, 2008). ER stress is also known as the unfolded protein response (Ron & Walter, 2007). In addition to contributing to inflammation via PERK‐dependent IKK activation (Jiao et al., 2011), ER stress also modify free fatty acids and adipokine secretion from adipose tissue (Xu, Spinas, & Niessen, 2010). As a critical modulator of SOCE, TRPC1/5 exerts an important role in the maintenance of cellular Ca²⁺ homeostasis and inhibit ER stress (Sukumaran, Schaar, Sun, & Singh, 2016), which accounting for the increased lipolysis and reduced adiponectin synthesis and secretion in obesity (Torre‐Villalvazo et al., 2018). TRPC1 protects against ER stress by maintaining ER Ca²⁺ homeostasis and its dysfunction results in prolonged activation of the unfolded protein response (UPR) pathway and impairs AKT activation (Harding, Calfon, Urano, Novoa, & Ron, 2002). And the overexpression of functional TRPC1 protects against neurotoxin‐induced ER stress and UPR by restoring AKT/mTOR signaling (Selvaraj et al., 2012). These beneficial effects of TRPC1 on antagonizing ER stress seems contradictory to its promotional role in obesity, implying that there exist some other underlying mechanisms (Figure 2).

Figure 2.

Ca²⁺‐influx mechanisms mediated by TRPC channels in adipocytes. Depletion of Ca²⁺ in the ER causes clustering of STIM1 in the ER membrane proximal to the plasma membrane, where they interact with ORAI1 to promote Ca²⁺ influx. This ORAI1‐mediated Ca²⁺ entry further stimulates TRPC1 channels to translocate into the plasma membrane where they stimulate a secondary Ca²⁺ influx event, which inhibits the secretion of adiponectin and ER stress. ER: endoplasmic reticulum [Color figure can be viewed at wileyonlinelibrary.com]

Unlike TRPVs, TRPCs display an almost similar preference for either divalent or monovalent cations, especially TRPC1/5 (Owsianik, Talavera, Voets, & Nilius, 2006), suggesting that Na⁺ would also actively enter into adipocytes when TRPC1/5 opens. In addition to be a well‐known independent risk factor for the development of cardiovascular diseases, high salt intake also displays a close link with obesity. Clinical studies have indicated that overweight and obese individuals are prone to consume more dietary salt, and their BMI are correlated with increased salt intake (X. Chen et al., 2015). Consuming 1 g more salt would result in an 28% increase risk of obesity in children and 26% in adult, with a significant relationship between salt consumption and fat mass (Y. Ma, He, & MacGregor, 2015). An animal experiment also pointed out that high salt diet would increase the amount of WAT in rats (Fonseca‐Alaniz et al., 2007) and promote obesity by stimulating endogenous fructose production in mice (Lanaspa et al., 2018). Our recent studies also confirm that increased salt intake among overweight/obese individuals is associated with altered salt sensitivity and preference, which could be blocked by capsaicin administration (Li, Cui et al., 2017; Li, Jin et al., 2017). We also observed that after long‐term high salt diet, there was a significant increase of the sodium content in adipose tissue of mice, especially perirenal adipose tissue (Zhao et al., 2016). Although TRPC1 is a critical regulator of SOCE by interacting with ORAI1 and STIM1 (Eder, 2017), knockdown of ORAI1 or pharmacological abrogation of plasma membrane Ca²⁺ entry and Ca²⁺ release from the ER did not affect its regulatory effects on some other functions, suggesting that the role of TRPC1 in modulating cell function could be also mediated by Na⁺ entry through these channels (Stolwijk et al., 2016). Therefore, although TRPC1 has been reported to function as a major Ca²⁺ entry channel in adipocytes and promote high fat diet‐induced obesity (Krout et al., 2017), the direct role of TRPC1‐mediated Ca²⁺ entry in obesity remains debatable. In addition, Sukumar et al. (2012) observed that arising TRPC1‐mediated Ca²⁺ influx inhibited the generation of adiponectin from adipose tissue, however, the promotional effect of adiponectin on activating PGC‐1a and mitochondrial biogenesis is dependent on Ca²⁺ influx through adiponectin receptor 1 in skeletal muscle (Iwabu et al., 2010), suggesting that Ca²⁺ might exert different roles in regulating adiponectin pathway among different tissue types. Moreover, low dietary sodium or sodium restriction decrease plasma concentration of adiponectin, especially high molecular adiponectin, in healthy men (Krikken, Dallinga‐Thie, Navis, & Dullaart, 2012; Lely et al., 2007), very similar to the effect of low calcium on adiponectin (Banga et al., 2008). We also found that high sodium intake‐mediated adipose PPARδ activation increases adiponectin level (Zhao et al., 2016), similar to the phenomenon observed in rats (Kamari et al., 2010). Others also reported a negative relationship between sodium intake and plasma adiponectin level in obesity (Baudrand, Campino et al., 2014; Baudrand, Lian et al., 2014). These evidence suggest that both increased Ca²⁺ and Na⁺ entry by TRPC1 might participate in its function on obesity, and this characteristic possessed by TRPC1/5 might also account for its discrepancy of action mode with TRPVs, however, it remains challenging to separate the contributions of Ca²⁺ versus Na⁺ signals generated by TRP channels in their effects on obesity.

5. TRPM8 AS A COLD SENSOR TO STIMULATE THERMOGENESIS IN BAT

TRPM8 is the only TRP channel displaying a central role in cold temperature detection. It is expressed in a small subset of temperature‐sensing neurons (Nilius et al., 2007; Voets et al., 2004). TRPM8 channels are steeply activated by cold temperature below 26–28°C (De la peña, Mälkiä, Cabedo, Belmonte, & Viana, 2005), and some cooling agents, such as menthol and icilin (Mahieu et al., 2007; Peier et al., 2002). We have first reported that TRPM8 is functionally present in mouse BAT. And long‐term dietary menthol intervention significantly increased the core temperatures and locomotor activity in mice by activation of TRPM8, accompanied by an enhanced UCP1 expression and PKA activation in BAT (S. Ma et al., 2012). The induction of "brown‐like" phenotype in WAT after TRPM8 activation was also determined in human (Rossato et al., 2014), whereas streptomycin antagonized TRPM8‐mediated calcium entry to mitigate mitochondrial uncoupled respiration, indicating that TRPM8 is involved in the priming of mitochondria to perform uncoupled respiration (Goralczyk et al., 2017). Similar to TRPV1, TRPM8 has also been reported to participate in the regulation of clock and clock‐controlled genes in BAT. BAT circadian clock is disrupted in the absence of TRPM8, accompanied by a reduced UCP1 expression level (Moraes, de Assis et al., 2017). Interestingly, a whole exome sequencing of the protein‐coding regions in the exome of obese subjects also identified TRPM8 as a gene responsible for obesity, by regulation of feeding behavior and EE (Kaewsutthi et al., 2016), suggesting a potential therapeutic value of TRPM8 in counteracting obesity in human.

6. OTHER TRP MEMBERS DISPLAYING POTENTIAL EFFECTS ON ADIPOSITY

The 2, 4, 5, 6, and 7 of TRPM channels are widely expressed in human CNS and periphery tissues (Fonfria et al., 2006). Among them, TRPM2 mRNA was also detected in adipose tissue and its expression was significantly decreased in WAT from HFD‐induced obese mice and db/db mice (Bishnoi et al., 2013; Sun et al., 2017). Zhang et al. have reported that TRPM2‐KO mice were more insulin sensitive and resistant to diet‐induced obesity, and this was due to increased EE and elevated browning of WAT. In addition, obesity‐mediated inflammation in adipose tissue and liver was attenuated in TRPM2‐KO mice (Z. Zhang et al., 2012), implying that the function of TRPM2 in adipocytes is similar to TRPV4.

TRPM7 is constitutively expressed, and its expression levels are highest in heart, liver, bone, and adipose tissue (Fonfria et al., 2006). Its global deletion results in embryonic lethality in mice, indicating an essential role in embryonic development (Jin et al., 2008; Ryazanova et al., 2010). TRPM7 conducts Zn²⁺ more than Mg²⁺ or Ca²⁺ and senses ROS to release Zn²⁺ from intracellular storage vesicles that contain the majority of TRPM7 protein (Abiria et al., 2017; Krapivinsky, Krapivinsky, Manasian, & Clapham, 2014). Although TRPM7 itself is not a SOC channel, pharmacological and molecular inhibition of TRPM7 kinase activity reduces SOCE (Faouzi, Kilch, Horgen, Fleig, & Penner, 2017). Altered expression or activity of TRPM7 is involved in several pathological conditions by regulating Mg²⁺ influx (Visser, Middelbeek, van Leeuwen, & Jalink, 2014). However, there are only some preliminary studies on the role of TRPM7 in adipocytes. Only one study reports that silencing TRPM7 reduced proliferation and decreased adipogenic differentiation of human or 3T3‐L1 preadipocytes by reducing p‐Akt kinase (Che, Yue, Tse, & Li, 2014; K. H. Chen et al., 2014).

TRPP is considered to be a nonselective ion channel protein associated with autosomal dominant polycystic kidney (ADPKD), including TRPP2 (PKD2, polycystin‐2), TRPP3 (PKD2L1, polycystin‐L), and TRPP5 (PKD2L2) (Moran, Xu, & Clapham, 2004). Although TRPP2 has been determined to be expressed in adipose tissue and its expression is higher in mature adipocytes compared to preadipocytes (Bishnoi et al., 2013; Sukumar et al., 2012), the direct role of TRPP2 in obesity has not been investigated yet. Interestingly, recent clinical studies have observed that patients with ADPKD often possess a higher prevalence of obesity, total cholesterol level as well as triglyceride levels (Bajrami, Idrizi, Roshi, & Barbullushi, 2016). In addition, overweight and, particularly, obesity is strongly and independently associated with the rate of progression in early‐stage ADPKD (Nowak et al., 2018). These findings imply that TRPP2 might also be involved in the development of obesity. TRPP3, also known as PKD2L1, is expressed in multiple tissues (Basora et al., 2002), and its activity is increased upon hypotonic stress and by alkalization (Shimizu, Janssens, Voets, & Nilius, 2009). Goralczyk et al. have detected comprehensive expression profile of all TRP genes in mesenchymal progenitor cells during white or brown adipogenesis. They found that knockdown of TRPP3 repressed the expression of the UCP‐1 and PGC‐1α as well as attenuated forskolin‐stimulated uncoupled respiration without affecting indices of generalized adipogenesis, indicating that TRPP3 facilitates BAT differentiation by enhancing mitochondrial function (Goralczyk et al., 2017).

As the second functional Ca²⁺ pool in the cell, Ca²⁺ uptake in isolated mitochondria was directly measured for the first time more than 50 years ago (Deluca & Engstrom, 1961). As Ca²⁺ is required for activation of three matrix dehydrogenases, pyruvate dehydrogenase phosphatase, a‐ketoglutarate dehydrogenase, and isocitrate dehydrogenase, mitochondrial Ca²⁺ flux is a critical regulator of aerobic metabolism by maintaining the activity of the citric acid cycle and the synthesis of NADH and ATP (Rizzuto et al., 2012). On the other hand, excessive Ca²⁺ accumulation leads to mitochondrial dysfunction by increasing mitochondrial ROS production and opening of the mitochondrial permeability transition pore, accompanied by collapse of membrane potential and mitochondrial swelling (Kowaltowski, de Souza‐Pinto, Castilho, & Vercesi, 2009; Peng & Jou, 2010). Mitochondria play a central role in metabolism of adipose tissue by controlling lipid metabolism pathways and converting mitochondrial energy into heat (Cedikova et al., 2016). The direct role of mitochondria‐localized TRP members in adipose tissue has not been reported yet, however, both TRPC3 and TRPV1 have been observed in mitochondria and controlling mitochondrial Ca²⁺ uptake or the activity of oxidative phosphorylation chain (Feng et al., 2013; Lang et al., 2015). Recently, we also discovered a critical role of mitochondrial TRPP3 in regulation of Ca²⁺ homeostasis in cardiomyocytes (Lu et al., 2018). TRPM8 channels were also found to locate in ER where they facilitated Ca²⁺ influx from ER to mitochondria in vascular smooth muscle cells (Xiong et al., 2017). These findings suggest that TRP channels might also directly affect adipocyte differentiation or maturation by modulating mitochondrial Ca²⁺ level. Therefore, it is worthwhile to further identify the mitochondria‐located TRP members and explore their functions in adipose tissue.

7. TRP CHANNELS AS POTENTIAL INTERVENTION TARGETS IN CLINICAL PRACTICE

In recent years, the TRP channels have attracted wide attention due to their potential clinical application. It has been found that foods in daily use contain a variety of active ingredients that regulate the expression or function of TRP channels. For example, capsaicin from chillies, piperine from black pepper, gingerol from ginger, eugenol from clove and capsinoids activate TRPV1, Δ9‐tetrahydro‐cannabinol, and cannabinol from cannabis are activators of TRPV2. Thymol from thyme and carvacrol from clove regulate TRPV3, while apigenin activates TRPV4. The activators of TRPM8 contain a variety of natural products, including menthone and menthol from mint, eucalyptol from essential oils from Eucalyptus polybractea, geraniol from lemongrass and aromatic herb oils, l‐carvone from spearmint or Kuromoji oil and hydroxyl‐citronellal from citronella oils, volatile oils such as lemon, lemongrass or melissa oils. In contrast, omega‐3 polyunsaturated fatty acids such as α‐linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid have been reported to exert inhibitory effect on TRPC1/5 (Bishnoi, Khare, Brown, & Panchal, 2018). Most of them have been shown to improve metabolism and inhibit obesity and obesity‐related diseases in rodents, however, only capsaicin and capsinoid have been tested in humans. Among them, capsaicin was the most studied. We and others have focused on the effect of capsaicin on metabolic diseases and pointed out that the habitual consumption of spicy foods was associated with a lower prevalence of obesity in humans (Ludy, Moore, & Mattes, 2012; Sun et al., 2016; Zsombok & Derbenev, 2016). Similar to capsaicin, consumption of Grains of Paradise, which contains 6‐gingerol increased whole‐body EE in human individuals with metabolically active BAT (Sugita et al., 2013). Ingestion of a capsaicin analog, capsinoid, increases EE and promotes fat acid oxidation through the activation of BAT in humans, particularly those with high BMI (Inoue, Matsunaga, Satoh, & Takahashi, 2007; Yoneshiro, Aita, Kawai, Iwanaga, & Saito, 2012). However, a hypoenergetic diet rich in α‐linolenic acid failed to affect body weight and fat mass of overweight and obese patients in a clinical trial (Egert et al., 2018). It should be also noticed that the in vivo effects of these various agents are not necessarily directly on adipocytes, some effects might be indirect via unknown mechanisms or mediators from other types of cell. Therefore, the translation of TRP channels to prevention or therapeutic treatment of obesity in humans by dietary constituents still needs further pursuing.

8. SUMMARY

Many TRP channels have been found to be localized to adipose tissue, where they function as modulators of the differentiation, proliferation, metabolism and some other biological behaviors of adipocytes to participate in the maturation/browning of WAT and thermogenesis of BAT, thus exert protective or promotional effect on obesity (Figure 3). Adipose TRP members mainly function as cation channels to control the intracellular Ca²⁺ level, thus display diverse roles in either inhibition or promotion of differentiation and maturation of adipocytes depending on the different stages of differentiation process. Functional studies also suggest that many TRP members are not simply passive cation channels, but instead they actively transport between plasma membrane and some intracellular organelles to modulate the Ca²⁺ homeostasis and affect subsequent signaling pathways controlling several critical cell behaviors. Moreover, cation permeability, subcellular localization, post‐modification and interaction with other proteins all contribute to affect the biological features of TRPs and might account for the difference in their effects on obesity, suggesting that to fully elucidate the detailed work mode of TRPs might be more difficult than we estimated. However, as TRP channels are respond to several types of environmental stimuli, such as temperature, food ingredient and some toxins, further investigating the underlying mechanism of their effects on obesity would help not only better understanding how these factors affect obesity but also identification of more specific agonists and antagonists for TRP channels to prevent or cure obesity. In the future, more excellent research are expected and encouraged to promote the advancement of our knowledge of TRPs to better understanding their mechanism of action in adipocytes and exploring their potential clinical usage.

Figure 3.

Schematic representation of the main effects of adipocyte‐located TRP channels on differentiation of adipocytes. Brown adipocytes are derived from a Myf5‐expressing progenitor population, while a distinct population of Myf5^‐ cells give rise to inducible (beige/brite) brown adipocytes as well as to white adipocytes. Several intracellular molecules are critical to the development and maintenance of brown adipocyte differentiation, such as PRDM16, PGC‐1α, and UCP‐1. TRP channels act at distinct points of the processes involved in the differentiation of several types of adipocytes, including brown and white adipocytes, as well as the intermediate forms of adipocytes transitioning from white to inducible, beige/brite adipocytes. According to their diverse expression change during maturation of preadipocytes, TRP channels are classified into two groups. The expression levels of green color‐labeled TRP members, including TRPV1/3, TRPP3 and TRPM8, are reduced, while that of others labeled with red color are increased during maturation of preadipocytes. TRPV1, TRPP3 and TRPM8 promote differentiation of brown adipocytes and induce browning of white adipocytes through activation of PRDM16, PGC‐1α, and UCP‐1, which could be inhibited by TRPV4. TRPV2 also displays a similar effect to TRPV1, whereas TRPM2 reduces the browning of white adipocytes. In addition, TRPC1/5 and TRPM7 facilitate the adipogenic differentiation of preadipocytes and promote obesity, which could be blocked by TRPV3 [Color figure can be viewed at wileyonlinelibrary.com]

AUTHOR CONTRIBUTIONS

P. G. and Z. Z. designed the scope of the review; P. G. performed the document searching and wrote the paper; P. G., Z. Y., and Z. Z. revised the paper.

CONFLICTS OF INTEREST STATEMENT

The authors declare that they have no conflicts of interest.