Open access peer-reviewed chapter

CAP and Metabolic Diseases: A Mini Review on Preclinical Mechanisms and Clinical Efficacy

Written By

Baskaran Thyagarajan, Vivek Krishnan and Padmamalini Baskaran

Submitted: 22 April 2018 Reviewed: 07 May 2018 Published: 01 August 2018

DOI: 10.5772/intechopen.78353

From the Edited Volume

Capsaicin and its Human Therapeutic Development

Edited by Gyula Mozsik

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Abstract

Capsaicin (CAP) is the chief active ingredient of natural chili peppers. It has culinary and medicinal benefits. CAP activates its receptor, transient receptor potential vanilloid subfamily 1 (TRPV1), which is expressed in the sensory and motor neurons, adipocytes, liver, vascular smooth muscle cells, neuromuscular junction, skeletal muscle, heart and brain. The specificity of CAP to activate TRPV1 is the fundamental mechanism for its medicinal benefits to treat pain, obesity, hypertension, and other diseases. Preclinical data from rodent model of high fat diet-induced obesity collectively suggest that CAP exerts its effects by activating TRPV1 signaling pathway, which stimulates thermogenic mechanisms in the white and brown adipose tissues to induce browning of white adipose tissues and brown adipose tissue thermogenesis. This leads to enhancement of metabolic activity and thermogenesis to counter obesity. Although CAP and its pungent and non-pungent analogs are used in human clinical studies, their effects on satiety and energy expenditure have been the highlights of such studies. The precise mechanism of action of CAP has not been evaluated in humans. This article summarizes these data and suggests that long-term safety and tolerance studies are important for advancing CAP to treat human obesity.

Keywords

  • capsaicin
  • TRPV1
  • weight gain
  • obesity
  • adipose tissue
  • browning
  • brite
  • chili peppers
  • satiety
  • energy expenditure

1. Introduction

Capsaicin (CAP) is the most commonly occurring capsaicinoids in chili peppers. It is enriched in the pith and ribs of the pepper. The pungency and heat of CAP give a prominent place as a chief spice ingredient in food industry. Chili peppers contain both pungent CAPoids and non-pungent capsinoids (Figure 1). CAP and dihydrocapsaicin belong to the group of pungent capsaicinoids, while non-pungent capsinoids like capsiate, dihydrocapsiate and nordihydrocapsiate have also been shown in preclinical studies to be beneficial against metabolic diseases. Chemically, CAP is known as 8-Methyl-N-vanillyl-trans-6-nonenamide. Biologically, CAP binds to and activates its receptor transient receptor potential vanilloid subfamily 1 (TRPV1) predominately expressed at the sensory nerve endings. Activation of TRPV1 by CAP is responsible for the intense heat and burning. CAP desensitizes TRPV1 and exerts its analgesic activity.

Figure 1.

Structure of capsinoids and capsaicinoids.

1.1. TRPV1: capsaicin receptor

TRPV1 is the first member of the vanilloid subfamily of the TRP superfamily of proteins. It is a non-selective cation channel protein discovered by Michael Caterina [1]. TRPV1 consists of six transmembrane domains, with intracellular N and C termini. The ion channel pore region is situated between the fifth and sixth transmembrane domains. Although CAP and resiniferatoxin are exogenous activators of TRPV1, it is endogenous activation is regulated by heat (~43°C), acidic pH (~5.5) and by inflammation mediators. Primarily, the expression of TRPV1 is recognized in sensory neurons. Published literature suggests that TRPV1 is also expressed in various other tissues such as the neuromuscular junction [2, 3, 4], adipose tissue [5, 6, 7], liver [8, 9], skeletal muscle [10, 11], vascular smooth muscle [12], etc. Also, published work suggests that TRPV1 in the brain. TRPV1 is involved in experimental model of temporal lobe epilepsy (TLE) [13]. Although TRPV1 expression has been reported in some brain areas [14], it is still highly controversial. Nonetheless, the activation of TRPV1 and its ability to sense pain signaling mechanism make it a valuable target for treating pain in humans.

Recent research has dramatically advanced TRPV1 as a target for treating various human diseases. Table 1 describes a list of preclinical and clinical studies for the beneficial effects of CAP against diseases.

Topical cream
0.01 or 0.025% for 6 weeks [15]
Psoriasis vulgarisBeneficial
Topical cream
0.075% for 8 weeks [16]
Painful diabetic neuropathyBeneficial
Topical cream
0.05% for several days [17]
Idiopathic trigeminal neuralgiaBeneficial
Topical cream: 0.075% [18] or 0.025% for 2 months [19]Post mastectomy pain syndromeBeneficial
Topical cream
0.025% for 7 days [20]
Cluster headachesBeneficial
Topical cream
0.025% for 3 weeks [21]
Solar (brachioradial) pruritusBeneficial
Oral candy (taffy): 5–9 ppm [22]Oral mucositis painBeneficial
Topical cream
0.075% for 4, 8 and 12 weeks [23]
Chronic distal painful polyneuropathyNo beneficial effects
Intravesical injection 2 mM [24]Chronic traumatic spinal detrusor hyperreflexiaBeneficial
Intravesical injection
10 μM for 1 month (twice weekly) [25]
Severe bladder painNo Beneficial effects
Intranasal solution (0.1 mMol/L) every 2 or 3 days. Seven total treatments [26]Non-allergic, non-infectious perennial rhinitisNo beneficial effects
Topical cream: 0.075% for 8 weeks [27] or 0.025% for 4 weeks [28]Neuropathic painBeneficial
Intravesical solution: 100 ml of 2 mM for 30 min. [29]Refractory detrusor hyperreflexiaBeneficial
Topical: 0.025% for 4 weeks [30]Atypical odontalgiaBeneficial
Topical cream: 5–10% [31]Refractory painBeneficial
Topical cream: 0.075% for 4 weeks (four times a day) [32]HIV-associated distal symmetrical peripheral neuropathyNo beneficial effects
Intravesical solution (Pelargonic acid vanillamide): 0.5 ml of 0.1 mmol/L solution per administration. Seven times in 14 days [33]Perennial allergic rhinitisNo beneficial effects
Topical cream
0.025% for 6 weeks [34]
Painful osteoarthritisBeneficial
Topical cream: 0.025–0.3% for 2 weeks to 4 months [35]Prurigo nodularisBeneficial
Oral red pepper powder
5 g/day for 5 weeks [36]
Functional dyspepsiaBeneficial
Topical liniment
0.05% for 5 days (three times a day) [37]
Hemodialysis-related pruritusBeneficial
Topical ointment
0.006% for 4 weeks [38]
Intractable pruritus aniBeneficial
Oral capsaicin 0.25% [39]Burning mouth syndromeBeneficial
Transdermal oleic capsaicin: containing patches 3 g per patch on 2 days with a 2-day interval between trials [40]Stable coronary disease (to improve ischemic threshold)Beneficial
Oral troche: 1.5 μg per troche. One troche per meal for 4 weeks [41]Swallowing dysfunctionBeneficial
Topical cream
0.075% [42]
UV induced immunosuppressionBeneficial
Transdermal dermal patch: 640 μg/cm2, 8% w/w for 60 min [43]HIV-associated peripheral neuropathyBeneficial
Intraoperative wound instillation of ultra purified CAP instillation
1000 μg—single instillation [44]
Post herniotomy painBeneficial
Topical ointment: 0.03% for 4 weeks (four times a day) [45]Uremic pruritusBeneficial
CAP dermal patch: 8 or 0.04% for 30, 60 and 90 min [46]Post herpetic neuralgiaBeneficial
Topical capsaicin cream
0.05% for 3 weeks (thrice a day) [47]
Chronic soft tissue painBeneficial
Topical civamide cream: 0.075% for 12 weeks (thrice a day) [48]Osteoarthritis of the kneeBeneficial
CAP hydrogel patch: 0.1% for 4 weeks (12 h a day) [49]Myofascial neck painNo beneficial effects
CAP cutaneous patch: 8% for 30 to 60 min [50]Peripheral neuropathic painBeneficial
CAP Cutaneous patch 8% for 60 min [51]Persistent inguinal postherniorrhaphy painNo beneficial effects
Topical CAPoid cream 0.01% nonivamide for 30 min a day for 21 days [52]Chronic low back painBeneficial
Oral capsules 0.4 mg per capsule (once daily for 2 weeks followed by twice daily for 2 weeks) [53]Chronic coughBeneficial
Oral Yanjiao 425 chili peppers containing 4 mg/g of CAP
1.25 g per day for 4 weeks [54]
Gestational diabetes mellitusBeneficial
Topical liposomal CAP
0.025% for two 6-week blocks with a gap of 2 weeks [55]
Post-herpetic neuralgiaNo beneficial effect
CAP cutaneous patch
8% for 60 min [56]
Lumbosacral painBeneficial
CAP cutaneous patch
8% for 30 min [57, 58]
Neuropathy and painful diabetic peripheral neuropathyBeneficial
Topical CAP gel: 0.01% or 0.025% for 14 days (thrice a day) [59]Burning mouth syndromeBeneficial

Table 1.

Capsaicin (type and dose) target disease effect.

Also, several preclinical and clinical studies have indicated that either capsiate alone or in combination with CAP is beneficial to counteract obesity and increase energy utilization [60, 61, 62, 63, 64]. However, the mechanisms behind such effect of CAP or capsiate still remain elusive.

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2. Obesity and metabolic dysfunction

Obesity is a major health care issue in the world. About one third of the world’s population is either obese or overweight. When energy intake exceeds energy expenditure, the excess energy is stored as triglycerides in the white adipose tissues. This leads to increase in adiposity, which presents glucose intolerance, insulin resistance, dyslipidemia and metabolic dysfunctions. Thus, diet-induced obesity progressively leads to type 2 diabetes, hypertension, hypercholesterolemia, and cardiovascular diseases. Although diet restriction and exercise are good strategies to combat obesity, lack of consistent motivation to stick to healthy diet and regular exercise regimen leads to rebound weight gain when such interventions are stopped. Further, the pharmacotherapy for weight loss is associated with toxicities and side effects [65, 66, 67, 68]. Bariatric surgeries are invasive procedures, not easily reversible but associated with high cost and potentials for adverse events.

2.1. CAP for obesity

There are overwhelming evidences for the effectiveness of CAP, its analogs and the whole chili pepper to ameliorate diet-induced obesity in rodents and humans [5, 69, 70, 71, 72]. Majority of these research studies have been directed to analyze broader outcome in terms of increase in energy expenditure, metabolic activity or measurement of weight loss. Scientific research unambiguously supports the concept that activation of CAP receptor is important for the effect of CAP to counter diet-induce obesity [5, 6, 7, 73]. However, it still remains unclear whether TRPV1 expressed on adipose tissues or on the nerves that innervate the adipose tissues. Further, there is no direct evidence to either support or disregard the role of TRPV1 expressed in central nervous system in this process. Although further research is warranted to clarify these mechanisms, published research works unambiguously support the benefits of CAP in abating obesity and metabolic syndrome in rodent models and humans. This article will discuss mechanisms emerging from studies focused on rodent models of obesity, which have translational value and help to interpret such mechanisms relevance to humans.

2.2. CAP and satiety

Since CAP is a pungent principle in chili peppers, its pungency has been regarded to satiety. Published work suggests that decreased appetite and increased energy expenditure were observed in humans who received red pepper in diet [74]. However, the ability of nonivamide, a less pungent analog of CAP to reduce appetite [75] suggests that the pungency of CAP may not be directly related to the appetite regulation. Table 2 below summarizes the clinical data that on the appetite regulation of CAP in the form of chili pepper powder or analog.

Intraduodenal infusion of CAP 1.5 mg [76]Promoted satiety
Oral red chili peppers 1.03 g [77]Increase satiety
Oral red pepper 10 g [78, 79]Decreases appetite—Desire to consume fatty, salty, and sweet foods were decreased
Oral chili 30 g/day chili blend [80]No effect on energy intake
Oral CAP 135 mg/day [81]No effect on satiety and hunger
Oral CAP 1.03 mg [82]No effect on satiety

Table 2.

CAP (type and dose) effect on appetite.

One important point to remember is the form of CAP that is used for human studies that have yielded contradictory data on the effect of CAP on energy intake. The discrepancy in the quality and type of CAP and variability in the duration of exposure of CAP to participants make interpretation difficult. These studies also lack validations on the ability of the form or type of CAP to activate TRPV1. This must be addressed in future studies. Nonetheless, important questions regarding how CAP mediates satiety or enhances energy expenditure in humans still remain unclear. Research studies focusing the effect of CAP on animal models of obesity will be invaluable to analyze such mechanism(s).

2.3. Adipose depots, functions and TRPV1 expression

Obesity is characterized by increased adiposity. White adipose tissue (WAT) primarily performs the function of insulation and protection in the body, and is regarded as the store for fat as triglycerides. Brown adipose tissue (BAT) plays a critical role in expending energy as it burns the stored energy into heat by a process called thermogenesis. These adipocytes were classified based on their functions and they significantly differ in their mitochondrial content, expression of genes/proteins that regulate thermogenic mechanisms and their localization in the body. BAT represents a small portion depot located throughout the human body at numerous distinct places, especially within the chest (perivascular-around the aorta, common carotid artery, cardiac veins and brachiocephalic artery), visceral cavity and subcutaneous region. BAT occurs along hollowed tissues (heart, trachea, lungs and esophagus), and in the visceral region, it is present around colon pancreas, kidneys, adrenal, liver and spleen [83, 84, 85, 86, 87]. Recently, a third type of adipose tissue called beige tissue or brite (brown in white) has been recognized, which are derived from WAT but express BAT specific thermogenic genes and proteins. In mammals, the beige-able adipose tissue locations haven identified as subcutaneous, inguinal and visceral [88] in rodents and supraclavicular [88], perirenal, visceral and subcutaneous depots [89] in humans.

Recent research has also characterized the expression of TRPV1 in these tissues. TRPV1 expression has been shown on cultured adipocytes [90, 91, 92] and epididymal, subcutaneous and brown adipocytes [6, 7, 93]. The validation of expression of TRPV1 on adipose tissues suggests a plausible role of TRPV1 in the recruitment of BAT activity and thermogenesis and the induction of the molecular conversion of WAT to beige like cells.

2.4. CAP and browning of white adipose tissue

Beige adipose tissue is characterized by the enhanced expression of thermogenic genes and proteins that are not usually expressed at a higher level in WAT. They show enhanced expression of mitochondrial uncoupling protein-1 (UCP-1), bone morphogenetic protein 8b (BMP8b), and central metabolic sensor, sirtuin-1 (SIRT-1), peroxisome proliferator activated receptor gamma (PPARγ) and PR domain 16 containing protein (PRDM-16) and PPARγ coactivator 1α (PGC-1α), which are recognized as factors regulating the beiging of WAT [94, 95]. Further, published literature suggests that Cd137 [96], Shox2 [97], Cited 1 [88], Tmem26 [96], Tbx1 [96, 98], Bmp8b [99, 100, 101], ucp-1 [102, 103], SIRT-1-dependent mechanisms [6, 104], are considered as markers for browning of WAT. Research work suggests that posttranslational modification, such as deacetylation, of PPARγ and PRDM-16 by SIRT-1 is involved in the beiging of WAT [6]. The deacetylation and stabilization of PPARγ and PRDM-16 by SiRT-1 been shown to induce browning of WAT in rodents [6, 7, 104]. CAP has been shown to induce browning of WAT in vitro [105] and in vivo [6] by activating SiRT-1 [6].

SiRT-1 plays a pivotal role in the regulation of cellular energy homeostasis. The phosphorylation and activation of SiRT-1 by cellular protein kinases like Ca2+/calmodulin-dependent protein kinase kinase β {CaMKKβ [106]}, CaMKIIα [6] and 5′-adenosine monophosphate-activated protein kinase {AMPK [6, 107, 108, 109]} has been shown to be important for the effect of CAP in browning of WAT. Preclinical data in mouse model of obesity suggests that feeding a high fat diet inhibits the expression and activity of TRPV1 in WAT and dietary CAP reversed it. CAP stimulates a robust Ca2+ influx via TRPV1, which stimulates CaMKII/AMPK-mediated SiRT-1 phosphorylation. This subsequently deacetylates PPARγ and PRDM-16 and promotes their stabilization. Figure 2 describes SiRT-1-dependent mechanisms by which CAP enhances the deacetylation of PPARalha and PGC-1alpha to enhance fatty acid oxidation and mitochondrial biogenesis to promote the browning of WAT and counter obesity. However, such a mechanism has not been shown in humans and future studies are needed to address this.

Figure 2.

Mechanism by which CAP induces browning of WAT. CAP (CAP)-stimulated Ca2+ influx via TRPV1. Activates CaMKII/AMPK-dependent SiRT-1 activation. SiRT-1 deacetylates PPARalpha and PGC-1alpha. This increases fatty acid oxidation and mitochondrial biogenesis to promote browning of WAT, and counters diet-induced obesity.

2.5. CAP and BAT thermogenesis

Recognition of expression of TRPV1 in BAT poses important questions on the ability of CAP to enhance thermogenesis. Research approaches have aimed at activation of SiRT-1 [110, 111, 112], β3 adrenergic receptors [113, 114, 115], thyroid hormone, irisin [116, 117] and FGF21 [118] induction in BAT. Studies also suggest that secretory signaling mechanisms from muscle and liver, such as irisin and Fgf21 are also recognized humans [119]. In rodent model, TRPV1 activation protects against high fat diet-induced obesity by stimulating the expression of thermogenic genes and proteins in BAT [7, 105, 120, 121, 122]. Further, CAP enhances SiRT-1-depenent deacetylation and interaction of PPARγ and PRDM-16 in BAT [7].

The crosstalk between TRPV1 and beta-adrenergic action (possible mechanism illustrated in Figure 3) has been reported in the literature [123], which could influence an additive effect on the thermogenic mechanisms in BAT. Also, there are data suggesting that TRPV1 expressed on vagal afferents or intestinal mucosal afferents are important for the anti-obesity effect of CAP [124, 125]. Further studies are required to address these mechanisms.

Figure 3.

Model describing the neuronal effect of TRPV1. CAP (CAP) activates TRPV1 expressed in the innervating nerve of iWAT. This increases noradrenaline release, which activates β adrenergic receptors. The resultant Ca2+ influx enhances AMPK-dependent SiRT-1 activation. SiRT-1 deacetylates PPAR𝝲 and PRDM-16. This causes PPAR𝝲-PRDM-16 interaction leading to BAT activation, which stimulates thermogenesis to ameliorate diet-induced obesity.

Research studies are now beginning to address the physiological functions of TRPV1 in adipose tissues. TRPV1 activation has been suggested to regulate adipogenesis and thermogenic pathways. It is also possible that along with the expression of TRPV1 on adipose tissue membranes, the expression of TRPV1 on the nerves that innervate adipose tissues may contribute for the browning of WAT and BAT thermogenic mechanisms. This necessitates the development of mouse strains that lack TRPV1 in specific tissues. Such a tool will be invaluable to delineate the precise role of TRPV1 signaling in metabolic tissues.

2.6. Safety and toxicological analyses of CAP

Studies have also addressed to evaluate the short-term and long-term effects of CAP in rodents and humans. In mice, oral administration of semisynthetic powdered CAP at a dose of 0.3125% caused benign tumors in cecum [126], Chili pepper extract-fed orally at a dose of 800 mg/kg per day in male and 200 mg/kg/day in female showed no toxicity in mice [127]. Mice received CAP at a dose of 1.46 or 1.94 mg/kg by intraperitoneal injection showed increase in gastric cancer [128], while oral gavage of 2 and 10 mg/kg of CAP showed chemoprevention against tumorigenesis [129]. Studies have also demonstrated the oral LD50 of CAP for mouse and rat were 161.2 and 118.8 mg/kg, respectively, [130]. Studies in humans suggest that feeding CAP in Women with gestational diabetes mellitus improved postprandial hyperglycemia, hyperinsulinemia, and fasting lipid disorders [54]. Also, CAP inhalation for cough challenge test had no single serious adverse event associated with CAP [131]. Further, a study in humans suggests that oral administration of 2.56 mg of CAP with every meal increased satiety and fullness and prevented over eating [77]. However, recent studies show that when along with a high fat diet CAP did not alter energy intake in mouse [6, 7]. However, there is still lack of clear evidence for the long-term effectiveness and safety of CAP in humans. Further studies are required to address this.

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3. Conclusions and future perspectives

This article summarizes the preclinical and clinical data, which collectively suggest the anti-obesity effect of CAP. However, the long-term efficacy and safety of TRPV1 agonist remain to be established. Although CAP is a natural product, its pungency is considered as a limitation for oral use. Therefore, research should be geared to develop approaches to mask the pungency of CAP by coating it with polymers of agents, which decrease its burst release in the oral cavity and in the gastrointestinal tract. Since non-pungent analogs have been shown to be effective, efforts should be made to enhance their bioavailability and stability in the body. For example, capsiate, a non-pungent analog of CAP, is effective [62, 64, 132, 133] but issues exist on its stability [134], which requires attention. Recently, a site-specific delivery system for CAP magnetic nanoparticles for obesity management has been reported [135, 136]. Such approaches should help in advancing the therapeutic efficacy of CAP. Further, efforts to deliver CAP at specific sites in the gastrointestinal tract through formulations such as enteric coated tablets and capsules will be beneficial to prevent its burst release in the stomach. Since human clinical study meta-analyses suggest that both CAPoids and capsinoids are beneficial in enhancing energy expenditure [64], dose products to combine them to counter obesity could be more effective.

Preclinical toxicological studies should be performed to demonstrate the safety and tolerance of CAP. These studies are important to clarify the perceptions that CAP could cause gastrointestinal disturbances and gastric ulcers [137, 138, 139, 140, 141, 142]. However, such studies should use quality controlled pure CAP instead of chili pepper powder since the quality of CAP in those powders depends on the source of the peppers. Further, establishing the proof of concept for the anti-obesity effect of CAP using a proper dose and delivery system and validation of its bioavailability and pharmacokinetics are important for advancing its use in humans to treat obesity and associated metabolic complications.

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Conflict of interest

The authors declare that there are no conflicts of interest.

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Abbreviations

CAPCapsaicin
TRPtransient receptor potential
TRPV1transient receptor potential vanilloid subfamily 1
SiRT-1sirtuin-1
PPARperoxisome proliferator activated receptor
PGC-1αPPARγ coactivator 1α
PRDM-16PR domain 16 containing protein
BMP8bbone morphogenetic protein 8b
UCP-1uncoupling protein 1
CaMKKβCa2+/calmodulin-dependent protein kinase kinase β
CaMKIICa2+/calmodulin dependent protein kinase II
AMPK5′-adenosine monophosphate activated kinase
WATwhite adipose tissue
BATbrown adipose tissue
LD50lethal dose 50

References

  1. 1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature. 1997;389(6653):816-824
  2. 2. Thyagarajan B, Krivitskaya N, Potian JG, Hognason K, Garcia CC and McArdle JJ. Capsaicin protects mouse neuromuscular junctions from the neuroparalytic effects of botulinum neurotoxin A. Journal of Pharmacology and Experimental Therapeutics. 2009 Nov;331(2):361-371
  3. 3. Baskaran P, Lehmann TE, Topchiy E, Thirunavukkarasu N, Cai S, Singh BR, Deshpande S, Thyagarajan B. Effects of enzymatically inactive recombinant botulinum neurotoxin type A at the mouse neuromuscular junctions. Toxicon. 2013;72:71-80
  4. 4. Thyagarajan B, Potian JG, Baskaran P, McArdle JJ. Capsaicin modulates acetylcholine release at the myoneural junction. European Journal of Pharmacology. 2014;744:211-219
  5. 5. Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circulation Research. 2007;100(7):1063-1070
  6. 6. Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. British Journal of Pharmacology. 2016;173(15):2369-2389
  7. 7. Baskaran P, Krishnan V, Fettel K, Gao P, Zhu Z, Ren J, Thyagarajan B. TRPV1 activation counters diet-induced obesity through sirtuin-1 activation and PRDM-16 deacetylation in brown adipose tissue. International Journal of Obesity. 2017;41(5):739-749
  8. 8. Li L, Chen J, Ni Y, Feng X, Zhao Z, Wang P, Sun J, Yu H, Yan Z, Liu D, Nilius B, Zhu Z. TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflügers Archiv. 2012;463(5):727-732
  9. 9. Baskaran P, Cook R, Cisneros S, McAllisted S, Thyagarajan B. N-HMME upregulates Lipolytic proteins in the liver to counter NAFLD. Biophysical Journal. 2016;110(3):25a
  10. 10. Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1alpha upregulation in mice. Cell Research. 2012;22(3):551-564
  11. 11. Krishnan V, Fettel K, Thyagarajan B. Dietary capsaicin and exercise: Analysis of a two-pronged approach to counteract obesity. Biophysical Journal. 2015;108(2):124a
  12. 12. Toth A, Czikora A, Pasztor ET, Dienes B, Bai P, Csernoch L, Rutkai I, Csato V, Manyine IS, Porszasz R, Edes I, Papp Z, Boczan J. Vanilloid receptor-1 (TRPV1) expression and function in the vasculature of the rat. The Journal of Histochemistry and Cytochemistry. 2014;62(2):129-144
  13. 13. Bhaskaran MD, Smith BN. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy. Experimental Neurology. 2010;223(2):529-536
  14. 14. Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, O'Donnell D, Nicoll RA, Shah NM, Julius D, Basbaum AI. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. The Journal of Neuroscience. 2011;31(13):5067-5077
  15. 15. Bernstein JE, Parish LC, Rapaport M, Rosenbaum MM, Roenigk HH Jr. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. Journal of the American Academy of Dermatology. 1986;15(3):504-507
  16. 16. Scheffler NM, Sheitel PL, Lipton MN. Treatment of painful diabetic neuropathy with capsaicin 0.075%. Journal of the American Podiatric Medical Association. 1991;81(6):288-293
  17. 17. Fusco BM, Alessandri M. Analgesic effect of capsaicin in idiopathic trigeminal neuralgia. Anesthesia and Analgesia. 1992;74(3):375-377
  18. 18. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: A randomized trial. Pain. 1992;51(3):375-379
  19. 19. Dini D, Bertelli G, Gozza A, Forno GG. Treatment of the post-mastectomy pain syndrome with topical capsaicin. Pain. 1993;54(2):223-226
  20. 20. Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13(2):114-116
  21. 21. Knight TE, Hayashi T. Solar (brachioradial) pruritus—Response to capsaicin cream. International Journal of Dermatology. 1994;33(3):206-209
  22. 22. Berger A, Henderson M, Nadoolman W, Duffy V, Cooper D, Saberski L, Bartoshuk L. Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. Journal of Pain and Symptom Management. 1995;10(3):243-248
  23. 23. Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O'Brien PC. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62(2):163-168
  24. 24. Geirsson G, Fall M, Sullivan L. Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia. The Journal of Urology. 1995;154(5):1825-1829
  25. 25. Lazzeri M, Beneforti P, Benaim G, Maggi CA, Lecci A, Turini D. Intravesical capsaicin for treatment of severe bladder pain: A randomized placebo controlled study. The Journal of Urology. 1996;156(3):947-952
  26. 26. Blom HM, Van Rijswijk JB, Garrelds IM, Mulder PG, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clinical and Experimental Allergy. 1997;27(7):796-801
  27. 27. Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, Wender DB, Rowland KM, Molina R, Cascino TL, Vukov AM, Dhaliwal HS, Ghosh C. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. Journal of Clinical Oncology. 1997;15(8):2974-2980
  28. 28. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: A randomized, double-blind, placebo-controlled study. British Journal of Clinical Pharmacology. 2000;49(6):574-579
  29. 29. De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert L, Fowler CJ. Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup. The Journal of Urology. 1997;158(6):2087-2092
  30. 30. Vickers ER, Cousins MJ, Walker S, Chisholm K. Analysis of 50 patients with atypical odontalgia. A preliminary report on pharmacological procedures for diagnosis and treatment. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 1998;85(1):24-32
  31. 31. Robbins WR, Staats PS, Levine J, Fields HL, Allen RW, Campbell JN, Pappagallo M. Treatment of intractable pain with topical large-dose capsaicin: Preliminary report. Anesthesia and Analgesia. 1998;86(3):579-583
  32. 32. Paice JA, Ferrans CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. Journal of Pain and Symptom Management. 2000;19(1):45-52
  33. 33. Gerth Van Wijk R, Terreehorst IT, Mulder PG, Garrelds IM, Blom HM, Popering S. Intranasal capsaicin is lacking therapeutic effect in perennial allergic rhinitis to house dust mite. A placebo-controlled study. Clinical and Experimental Allergy. 2000;30(12):1792-1798
  34. 34. McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: A randomized, double blind, placebo controlled study. European Journal of Pain. 2000;4(4):355-360
  35. 35. Stander S, Luger T, Metze D. Treatment of prurigo nodularis with topical capsaicin. Journal of the American Academy of Dermatology. 2001;44(3):471-478
  36. 36. Bortolotti M, Coccia G, Grossi G, Miglioli M. The treatment of functional dyspepsia with red pepper. Alimentary Pharmacology & Therapeutics. 2002;16(6):1075-1082
  37. 37. Weisshaar E, Dunker N, Gollnick H. Topical capsaicin therapy in humans with hemodialysis-related pruritus. Neuroscience Letters. 2003;345(3):192-194
  38. 38. Lysy J, Sistiery-Ittah M, Israelit Y, Shmueli A, Strauss-Liviatan N, Mindrul V, Keret D, Goldin E. Topical capsaicin—A novel and effective treatment for idiopathic intractable pruritus ani: A randomised, placebo controlled, crossover study. Gut. 2003;52(9):1323-1326
  39. 39. Petruzzi M, Lauritano D, De Benedittis M, Baldoni M, Serpico R. Systemic capsaicin for burning mouth syndrome: Short-term results of a pilot study. Journal of Oral Pathology & Medicine. 2004;33(2):111-114
  40. 40. Fragasso G, Palloshi A, Piatti PM, Monti L, Rossetti E, Setola E, Montano C, Bassanelli G, Calori G, Margonato A. Nitric-oxide mediated effects of transdermal capsaicin patches on the ischemic threshold in patients with stable coronary disease. Journal of Cardiovascular Pharmacology. 2004;44(3):340-347
  41. 41. Ebihara T, Takahashi H, Ebihara S, Okazaki T, Sasaki T, Watando A, Nemoto M, Sasaki H. Capsaicin troche for swallowing dysfunction in older people. Journal of the American Geriatrics Society. 2005;53(5):824-828
  42. 42. Howes RA, Halliday GM, Barnetson RS, Friedmann AC, Damian DL. Topical capsaicin reduces ultraviolet radiation-induced suppression of Mantoux reactions in humans. Journal of Dermatological Science (Netherlands). 2006 Nov;44(2):113-115
  43. 43. Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70(24):2305-2313
  44. 44. Aasvang EK, Hansen JB, Malmstrom J, Asmussen T, Gennevois D, Struys MM, Kehlet H. The effect of wound instillation of a novel purified capsaicin formulation on postherniotomy pain: A double-blind, randomized, placebo-controlled study. Anesthesia and Analgesia. 2008;107(1):282-291
  45. 45. Makhlough A, Ala S, Haj-Heydari Z, Kashi Z, Bari A. Topical capsaicin therapy for uremic pruritus in patients on hemodialysis. Iranian Journal of Kidney Diseases. 2010;4(2):137-140
  46. 46. Webster LR, Malan TP, Tuchman MM, Mollen MD, Tobias JK, Vanhove GF. A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. The Journal of Pain. 2010;11(10):972-982
  47. 47. Chrubasik S, Weiser T, Beime B. Effectiveness and safety of topical capsaicin cream in the treatment of chronic soft tissue pain. Phytotherapy Research. 2010;24(12):1877-1885
  48. 48. Schnitzer TJ, Pelletier JP, Haselwood DM, Ellison WT, Ervin JE, Gordon RD, Lisse JR, Archambault WT, Sampson AR, Fezatte HB, Phillips SB, Bernstein JE. Civamide cream 0.075% in patients with osteoarthritis of the knee: A 12-week randomized controlled clinical trial with a longterm extension. The Journal of Rheumatology. 2012;39(3):610-620
  49. 49. Cho JH, Brodsky M, Kim EJ, Cho YJ, Kim KW, Fang JY, Song MY. Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: A double-blinded randomized trial. Pain Medicine. 2012;13(7):965-970
  50. 50. Maihofner C, Heskamp ML. Prospective, non-interventional study on the tolerability and analgesic effectiveness over 12 weeks after a single application of capsaicin 8% cutaneous patch in 1044 patients with peripheral neuropathic pain: First results of the QUEPP study. Current Medical Research and Opinion. 2013;29(6):673-683
  51. 51. Bischoff JM, Ringsted TK, Petersen M, Sommer C, Uceyler N, Werner MU. A capsaicin (8%) patch in the treatment of severe persistent inguinal postherniorrhaphy pain: A randomized, double-blind, placebo-controlled trial. PLoS One. 2014;9(10):e109144
  52. 52. Horvath K, Boros M, Bagoly T, Sandor V, Kilar F, Kemeny A, Helyes Z, Szolcsanyi J, Pinter E. Analgesic topical capsaicinoid therapy increases somatostatin-like immunoreactivity in the human plasma. Neuropeptides. 2014;48(6):371-378
  53. 53. Ternesten-Hasseus E, Johansson EL, Millqvist E. Cough reduction using capsaicin. Respiratory Medicine. 2015;109(1):27-37
  54. 54. Yuan LJ, Qin Y, Wang L, Zeng Y, Chang H, Wang J, Wang B, Wan J, Chen SH, Zhang QY, Zhu JD, Zhou Y, Mi MT. Capsaicin-containing chili improved postprandial hyperglycemia, hyperinsulinemia, and fasting lipid disorders in women with gestational diabetes mellitus and lowered the incidence of large-for-gestational-age newborns. Clinical Nutrition. 2016;35(2):388-393
  55. 55. Teixeira MJ, Menezes LM, Silva V, Galhardoni R, Sasson J, Okada M, Duarte KP, Yeng LT, Andrade DC. Liposomal topical capsaicin in post-herpetic neuralgia: A safety pilot study. Arquivos de Neuro-Psiquiatria. 2015;73(3):237-240
  56. 56. Zis P, Bernali N, Argira E, Siafaka I, Vadalouka A. Effectiveness and impact of capsaicin 8% patch on quality of life in patients with lumbosacral pain: An open-label study. Pain Physician. 2016;19(7):E1049-E1053
  57. 57. Simpson DM, Robinson-Papp J, Van J, Stoker M, Jacobs H, Snijder RJ, Schregardus DS, Long SK, Lambourg B, Katz N. Capsaicin 8% patch in painful diabetic peripheral neuropathy: A randomized, double-blind, placebo-controlled study. The Journal of Pain. 2017;18(1):42-53
  58. 58. Mankowski C, Poole CD, Ernault E, Thomas R, Berni E, Currie CJ, Treadwell C, Calvo JI, Plastira C, Zafeiropoulou E, Odeyemi I. Effectiveness of the capsaicin 8% patch in the management of peripheral neuropathic pain in European clinical practice: The ASCEND Study. BMC Neurology. 2017;17(1):80
  59. 59. Jorgensen MR, Pedersen AM. Analgesic effect of topical oral capsaicin gel in burning mouth syndrome. Acta Odontologica Scandinavica. 2017;75(2):130-136
  60. 60. Haramizu S, Kawabata F, Ohnuki K, Inoue N, Watanabe T, Yazawa S, Fushiki T. Capsiate, a non-pungent capsaicin analog, reduces body fat without weight rebound like swimming exercise in mice. Biomedical Research. 2011;32(4):279-284
  61. 61. Huang W, Cheang WS, Wang X, Lei L, Liu Y, Ma KY, Zheng F, Huang Y, Chen ZY. Capsaicinoids but not their analogue capsinoids lower plasma cholesterol and possess beneficial vascular activity. Journal of Agricultural and Food Chemistry. 2014;62(33):8415-8420
  62. 62. Kwon DY, Kim YS, Ryu SY, Cha MR, Yon GH, Yang HJ, Kim MJ, Kang S, Park S. Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats. The Journal of Nutritional Biochemistry. 2013;24(6):1078-1085
  63. 63. Ludy MJ, Moore GE, Mattes RD. The effects of capsaicin and capsiate on energy balance: Critical review and meta-analyses of studies in humans. Chemical Senses. 2012;37(2):103-121
  64. 64. Zsiboras C, Matics R, Hegyi P, Balasko M, Petervari E, Szabo I, Sarlos P, Miko A, Tenk J, Rostas I, Pecsi D, Garami A, Rumbus Z, Huszar O, Solymar M. Capsaicin and capsiate could be appropriate agents for treatment of obesity: A meta-analysis of human studies. Critical Reviews in Food Science and Nutrition. 2016:1-9
  65. 65. Maksimov ML, Svistunov AA, Tarasov VV, Chubarev VN, Avila-Rodriguez M, Barreto GE, Dralova OV, Aliev G. Approaches for the development of drugs for treatment of obesity and metabolic syndrome. Current Pharmaceutical Design. 2016;22(7):895-903
  66. 66. Mordes JP, Liu C, Xu S. Medications for weight loss. Current Opinion in Endocrinology, Diabetes, and Obesity. 2015;22(2):91-97
  67. 67. Pagotto U, Vanuzzo D, Vicennati V, Pasquali R. Pharmacological therapy of obesity. Giornale Italiano Di Cardiologia (Rome). 2008;9(4 Suppl 1):83S-93S
  68. 68. Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: Focus on adverse side-effect profiles. Diabetes, Obesity & Metabolism. 2016;18(6):558-570
  69. 69. Zheng J, Zheng S, Feng Q, Zhang Q, Xiao X. Dietary capsaicin and its anti-obesity potency: From mechanism to clinical implications. Bioscience Reports. 2017 May 11:37(3). pii: BSR20170286
  70. 70. Bloomer RJ, Canale RE, Shastri S, Suvarnapathki S. Effect of oral intake of capsaicinoid beadlets on catecholamine secretion and blood markers of lipolysis in healthy adults: A randomized, placebo controlled, double-blind, cross-over study. Lipids in Health and Disease. 2010;9:72
  71. 71. Gunthorpe MJ, Szallasi A. Peripheral TRPV1 receptors as targets for drug development: New molecules and mechanisms. Current Pharmaceutical Design. 2008;14(1):32-41
  72. 72. Belza A, Jessen AB. Bioactive food stimulants of sympathetic activity: Effect on 24-h energy expenditure and fat oxidation. European Journal of Clinical Nutrition. 2005;59(6):733-741
  73. 73. Cioffi DL. The skinny on TRPV1. Circulation Research. 2007;100(7):934-936
  74. 74. Westerterp-Plantenga MS, Smeets A, Lejeune MP. Sensory and gastrointestinal satiety effects of capsaicin on food intake. International Journal of Obesity. 2005;29(6):682-688
  75. 75. Hochkogler CM, Rohm B, Hojdar K, Pignitter M, Widder S, Ley JP, Krammer GE, Somoza V. The capsaicin analog nonivamide decreases total energy intake from a standardized breakfast and enhances plasma serotonin levels in moderately overweight men after administered in an oral glucose tolerance test: A randomized, crossover trial. Molecular Nutrition & Food Research. 2014;58(6):1282-1290
  76. 76. van Avesaat M, Troost FJ, Westerterp-Plantenga MS, Helyes Z, Le Roux CW, Dekker J, Masclee AA, Keszthelyi D. Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones. The American Journal of Clinical Nutrition. 2016;103(2):305-313
  77. 77. Janssens PL, Hursel R, Westerterp-Plantenga MS. Capsaicin increases sensation of fullness in energy balance, and decreases desire to eat after dinner in negative energy balance. Appetite. 2014;77:44-49
  78. 78. Yoshioka M, St-Pierre S, Drapeau V, Dionne I, Doucet E, Suzuki M, Tremblay A. Effects of red pepper on appetite and energy intake. The British Journal of Nutrition. 1999;82(2):115-123
  79. 79. Ludy MJ, Mattes RD. The effects of hedonically acceptable red pepper doses on thermogenesis and appetite. Physiology & Behavior. 2011;102(3-4):251-258
  80. 80. Ahuja KD, Robertson IK, Geraghty DP, Ball MJ. The effect of 4-week chilli supplementation on metabolic and arterial function in humans. European Journal of Clinical Nutrition. 2007;61(3):326-333
  81. 81. Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. The British Journal of Nutrition. 2003;90(3):651-659
  82. 82. Smeets AJ, Westerterp-Plantenga MS. The acute effects of a lunch containing capsaicin on energy and substrate utilisation, hormones, and satiety. European Journal of Nutrition. 2009;48(4):229-234
  83. 83. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. The New England Journal of Medicine. 2009;360(15):1509-1517
  84. 84. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. The New England Journal of Medicine. 2009;360(15):1500-1508
  85. 85. Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerback S. Evidence for two types of brown adipose tissue in humans. Nature Medicine. 2013;19(5):631-634
  86. 86. Lee P, Greenfield JR, Ho KK, Fulham MJ. A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. American Journal of Physiology. Endocrinology and Metabolism. 2010;299(4):E601-E606
  87. 87. Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: Functional relevance and implications in obesity and type 2 diabetes. Diabetes. 2013;62(6):1783-1790
  88. 88. Harms M, Seale P. Brown and beige fat: Development, function and therapeutic potential. Nature Medicine. 2013;19(10):1252-1263
  89. 89. Rockstroh D, Landgraf K, Wagner IV, Gesing J, Tauscher R, Lakowa N, Kiess W, Buhligen U, Wojan M, Till H, Bluher M, Korner A. Direct evidence of brown adipocytes in different fat depots in children. PLoS One. 2015;10(2):e0117841
  90. 90. Sun W, Li C, Zhang Y, Jiang C, Zhai M, Zhou Q, Xiao L, Deng Q. Gene expression changes of thermo-sensitive transient receptor potential channels in obese mice. Cell Biology International. 2017;41(8):908-913
  91. 91. Kim M, Goto T, Yu R, Uchida K, Tominaga M, Kano Y, Takahashi N, Kawada T. Fish oil intake induces UCP1 upregulation in brown and white adipose tissue via the sympathetic nervous system. Scientific Reports. 2015;5:18013
  92. 92. Bishnoi M, Kondepudi KK, Gupta A, Karmase A, Boparai RK. Expression of multiple transient receptor potential channel genes in murine 3T3-L1 cell lines and adipose tissue. Pharmacological Reports. 2013;65(3):751-755
  93. 93. Moraes MN, Mezzalira N, de Assis LV, Menaker M, Guler A, Castrucci AM. TRPV1 participates in the activation of clock molecular machinery in the brown adipose tissue in response to light-dark cycle. Biochimica et Biophysica Acta. 2017;1864(2):324-335
  94. 94. Chi J, Cohen P. The multifaceted roles of PRDM16: Adipose biology and beyond. Trends in Endocrinology and Metabolism. 2016;27(1):11-23
  95. 95. Kuhn E, Binart N, Lombes M. Brown, white, beige: The color of fat and new therapeutic perspectives for obesity. Annales d'Endocrinologie. 2012;73(Suppl 1):S2-S8
  96. 96. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366-376
  97. 97. Servera M, Lopez N, Serra F, Palou A. Expression of “brown-in-white” adipocyte biomarkers shows gender differences and the influence of early dietary exposure. Genes & Nutrition. 2014;9(1):372
  98. 98. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. The Journal of Biological Chemistry. 2010;285(10):7153-7164
  99. 99. Martins L, Seoane-Collazo P, Contreras C, Gonzalez-Garcia I, Martinez-Sanchez N, Gonzalez F, Zalvide J, Gallego R, Dieguez C, Nogueiras R, Tena-Sempere M, Lopez M. A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Reports. 2016;16(8):2231-2242
  100. 100. Poher AL, Altirriba J, Veyrat-Durebex C, Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Frontiers in Physiology. 2015;6:4
  101. 101. Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Molecular and Cellular Endocrinology. 2015;402:86-94
  102. 102. Valero-Munoz M, Li S, Wilson RM, Hulsmans M, Aprahamian T, Fuster JJ, Nahrendorf M, Scherer PE, Sam F. Heart failure with preserved ejection fraction induces Beiging in adipose tissue. Circulation. Heart Failure. 2016;9(1):e002724
  103. 103. Srinivasa S, Wong K, Fitch KV, Wei J, Petrow E, Cypess AM, Torriani M, Grinspoon SK. Effects of lifestyle modification and metformin on irisin and FGF21 among HIV-infected subjects with the metabolic syndrome. Clinical Endocrinology. 2015;82(5):678-685
  104. 104. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, Accili D. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell. 2012;150(3):620-632
  105. 105. Baboota RK, Singh DP, Sarma SM, Kaur J, Sandhir R, Boparai RK, Kondepudi KK, Bishnoi M. Capsaicin induces “brite” phenotype in differentiating 3T3-L1 preadipocytes. PLoS One. 2014;9(7):e103093
  106. 106. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature. 2010;464(7293):1313-1319
  107. 107. Passariello CL, Zini M, Nassi PA, Pignatti C, Stefanelli C. Upregulation of SIRT1 deacetylase in phenylephrine-treated cardiomyoblasts. Biochemical and Biophysical Research Communications. 2011;407(3):512-516
  108. 108. Lau AW, Liu P, Inuzuka H, Gao D. SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation. American Journal of Cancer Research. 2014;4(3):245-255
  109. 109. Peng Y, Rideout DA, Rakita SS, Gower WR Jr, You M, Murr MM. Does LKB1 mediate activation of hepatic AMP-protein kinase (AMPK) and sirtuin1 (SIRT1) after Roux-en-Y gastric bypass in obese rats? Journal of Gastrointestinal Surgery. 2010;14(2):221-228
  110. 110. Yuan X, Wei G, You Y, Huang Y, Lee HJ, Dong M, Lin J, Hu T, Zhang H, Zhang C, Zhou H, Ye R, Qi X, Zhai B, Huang W, Liu S, et al. Rutin ameliorates obesity through brown fat activation. The FASEB Journal. 2017;31(1):333-345
  111. 111. Liu Z, Gu H, Gan L, Xu Y, Feng F, Saeed M, Sun C. Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. Oncotarget. 2017;8(6):9267-9279
  112. 112. Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metabolism. 2008;8(5):347-358
  113. 113. Richard D, Picard F. Brown fat biology and thermogenesis. Frontiers in Bioscience (Landmark Ed.). 2011;16:1233-1260
  114. 114. Takakura Y, Yoshida T. Beta 3-adrenergic receptor agonists--past, present and future. Nihon Yakurigaku Zasshi. 2001;118(5):315-320
  115. 115. Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiological Reviews. 1984;64(1):1-64
  116. 116. Castillo-Quan JI. From white to brown fat through the PGC-1alpha-dependent myokine irisin: Implications for diabetes and obesity. Disease Models & Mechanisms. 2012;5(3):293-295
  117. 117. Contreras C, Gonzalez F, Ferno J, Dieguez C, Rahmouni K, Nogueiras R, Lopez M. The brain and brown fat. Annals of Medicine. 2015;47(2):150-168
  118. 118. Giralt M, Gavalda-Navarro A, Villarroya F. Fibroblast growth factor-21, energy balance and obesity. Molecular and Cellular Endocrinology. 2015;418(Pt 1):66-73
  119. 119. Cereijo R, Giralt M, Villarroya F. Thermogenic brown and beige/brite adipogenesis in humans. Annals of Medicine. 2015;47(2):169-177
  120. 120. McCarty MF, DiNicolantonio JJ, O'Keefe JH. Capsaicin may have important potential for promoting vascular and metabolic health. Open Heart. 2015;2(1):e000262
  121. 121. Lee E, Jung DY, Kim JH, Patel PR, Hu X, Lee Y, Azuma Y, Wang HF, Tsitsilianos N, Shafiq U, Kwon JY, Lee HJ, Lee KW, Kim JK. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. The FASEB Journal. 2015;29(8):3182-3192
  122. 122. Baboota RK, Murtaza N, Jagtap S, Singh DP, Karmase A, Kaur J, Bhutani KK, Boparai RK, Premkumar LS, Kondepudi KK, Bishnoi M. Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice. The Journal of Nutritional Biochemistry. 2014;25(9):893-902
  123. 123. Oi-Kano Y, Iwasaki Y, Nakamura T, Watanabe T, Goto T, Kawada T, Watanabe K, Iwai K. Oleuropein aglycone enhances UCP1 expression in brown adipose tissue in high-fat-diet-induced obese rats by activating beta-adrenergic signaling. The Journal of Nutritional Biochemistry. 2017;40:209-218
  124. 124. Kentish SJ, Frisby CL, Kritas S, Li H, Hatzinikolas G, O'Donnell TA, Wittert GA, Page AJ. TRPV1 channels and gastric vagal afferent signalling in lean and high fat diet induced obese mice. PLoS One. 2015;10(8):e0135892
  125. 125. Leung FW. Capsaicin-sensitive intestinal mucosal afferent mechanism and body fat distribution. Life Sciences. 2008;83(1-2):1-5
  126. 126. Toth B, Gannett P. Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice. In Vivo. 1992;6(1):59-63
  127. 127. Chanda S, Erexson G, Riach C, Innes D, Stevenson F, Murli H, Bley K. Genotoxicity studies with pure trans-capsaicin. Mutation Research. 2004;557(1):85-97
  128. 128. Diaz Barriga Arceo S, Madrigal-Bujaidar E, Calderon Montellano E, Ramirez Herrera L, Diaz Garcia BD. Genotoxic effects produced by capsaicin in mouse during subchronic treatment. Mutation Research. 1995;345(3-4):105-109
  129. 129. Zhang Z, Huynh H, Teel RW. Effects of orally administered capsaicin, the principal component of capsicum fruits, on the in vitro metabolism of the tobacco-specific nitrosamine NNK in hamster lung and liver microsomes. Anticancer Research. 1997;17(2A):1093-1098
  130. 130. Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. International Journal of Toxicology. 2007;26(Suppl 1):3-106
  131. 131. Dicpinigaitis PV, Alva RV. Safety of capsaicin cough challenge testing. Chest. 2005;128(1):196-202
  132. 132. Yashiro K, Tonson A, Pecchi E, Vilmen C, Le Fur Y, Bernard M, Bendahan D, Giannesini B. Capsiate supplementation reduces oxidative cost of contraction in exercising mouse skeletal muscle in vivo. PLoS One. 2015;10(6):e0128016
  133. 133. Masuda Y, Haramizu S, Oki K, Ohnuki K, Watanabe T, Yazawa S, Kawada T, Hashizume S, Fushiki T, Thyagarajan B, Baskaran P. Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. Journal of Applied Physiology (1985). 2003;95(6):2408-2415
  134. 134. Iida T, Moriyama T, Kobata K, Morita A, Murayama N, Hashizume S, Fushiki T, Yazawa S, Watanabe T, Tominaga M. TRPV1 activation and induction of nociceptive response by a non-pungent capsaicin-like compound, capsiate. Neuropharmacology. 2003;44(7):958-967
  135. 135. Thyagarajan B, Baskaran P. Nanoparticle delivery system for targeted anti-obesity treatment. United States Patent No US9,782,481 B2. 2017
  136. 136. Thyagarajan B, Baskaran P. Nanoparticle delivery system for targeted anti-obesity treatment. United States Patent No US9,320,749 B2. 2016
  137. 137. Srinivasan K. Biological activities of red pepper (Capsicum annuum) and its pungent principle capsaicin: A review. Critical Reviews in Food Science and Nutrition. 2016;56(9):1488-1500
  138. 138. Mozsik G. Capsaicin as new orally applicable gastroprotective and therapeutic drug alone or in combination with nonsteroidal anti-inflammatory drugs in healthy human subjects and in patients. Progress in Drug Research. 2014;68:209-258
  139. 139. Luo XJ, Li NS, Zhang YS, Liu B, Yang ZC, Li YJ, Dong XR, Peng J. Vanillyl nonanoate protects rat gastric mucosa from ethanol-induced injury through a mechanism involving calcitonin gene-related peptide. European Journal of Pharmacology. 2011;666(1-3):211-217
  140. 140. Satyanarayana MN. Capsaicin and gastric ulcers. Critical Reviews in Food Science and Nutrition. 2006;46(4):275-328
  141. 141. Brzozowski T, Konturek SJ, Sliwowski Z, Pytko-Polonczyk J, Szlachcic A, Drozdowicz D. Role of capsaicin-sensitive sensory nerves in gastroprotection against acid-independent and acid-dependent ulcerogens. Digestion. 1996;57(6):424-432
  142. 142. Kang JY. Chilli, capsaicin and the stomach. Clinical Science (London, England). 1996;91(3):252-254

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Baskaran Thyagarajan, Vivek Krishnan and Padmamalini Baskaran

Submitted: 22 April 2018 Reviewed: 07 May 2018 Published: 01 August 2018