Obesity has become a global public health issue, with recent statistics indicating that over 1.9 billion adults were overweight and over 650 million were obese in 2016. Overweight and obesity are associated with multiple health problems, such as hypertension, type 2 diabetes mellitus, CHD, and cancers, which brings a heavy economic burden to families and society. Novel, individualized interventions may thus be necessary to effectively prevent and treat overweight and obesity, such as the phytochemicals extracted from plants. Capsaicin, the most important compound of chili pepper, is the major pungent principle in various species of capsicum fruits such as hot chili peppers and has long been globally used as an ingredient of spices, preservatives, and medicines. Given the increasing incidence of obesity annually, the resulting complications place heavy psychological and economic pressure on patients. Therefore, revealing the neuroendocrine regulatory mechanism of TRPV1 in obesity is particularly important.
The Role of Brown Fat and Thermogenesis
Brown fat, or brown adipose tissue (BAT), is a distinct type of fat that is activated in response to cold temperatures. Its primary role is to produce heat to help maintain body temperature, and it achieves that by burning calories. The capacity of brown and beige fat cells to burn fuel and produce heat, especially upon exposure to cold temperatures, has long made them an attractive target for treating obesity and other metabolic disorders. A new source of energy expending brown fat cells has been uncovered by Harvard Medical School researchers at Joslin Diabetes Center, which they said points towards potential new therapeutic options for obesity.
TRPV1-Positive Smooth Muscle Cells: A Novel Source of Brown Fat
Specifically, the authors point to smooth muscle cells expressing the Trpv1 (temperature-sensitive ion channel transient receptor potential cation subfamily V member 1) receptor and identify them as a novel source of energy-burning brown fat cells (adipocytes). The source of these energy-burning fat cells was previously considered to be exclusively related to a population of cells that express the receptor Pdgfrα (platelet-derived growth factor receptor alpha). However, wider evidence suggests other sources may exist.
The team initially investigated the general cellular makeup of brown adipose tissue from mice housed at different temperatures and lengths of time. Notably, they employed modern single-cell RNA sequencing approaches to try to identify all types of cells present. As well as identifying the previously known Pdgfrα-source of energy-burning brown fat cells, their analysis of the single-cell RNA sequencing data suggested another distinct population of cells doing the same job-cells derived from smooth muscle expressing Trpv1. Further investigations with mouse models confirmed that the Trpv1-positive smooth muscle cells gave rise to the brown energy-burning version of fat cells especially when exposed to cold temperatures. Further studies are now planned to address the role of the Trpv1 channel and its ligands and whether it is possible to target these cells to increase numbers of thermogenic adipocytes as a therapeutic approach towards obesity.
Capsaicin and Weight Management: A Meta-Analysis
Animal studies have shown that capsaicin plays a positive role in weight management. However, the results in human research are controversial. Therefore, a systematic review and meta-analysis aimed to evaluate the effect of capsaicin on weight loss in adults.
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Study Design and Methods
The published studies involving capsicum and obesity were searched through PubMed, Embase, China Biomedical Literature Database (CBM), Cochrane library, and clinical registration center, from database inception to 3 May 2022. The search was limited to studies in humans and published in English and Chinese. In addition, the literature traceability method and manual retrieval method were used to complete the search strategy. Studies retrieved that examined the association between supplementation with capsaicin and body composition, and metabolic profiles. Fifteen RCT with 762 individuals were included in the meta-analyses.
The inclusion criteria were as follows: (1) enrolled subjects aged 18 or older, no disease, but includes overweight and obese participants and (2) studies that were RCT, which is divided into the intervention group and the control group. The intervention group was supplemented with capsaicin or red pepper, and the control group is given a regular diet. (3) Long-term trials (time of duration ≥ 4 weeks), (4) studies with detailed sample size and outcome observations, (5) studies include at least one of the required outcomes (BMI, BW, WHR, WC).
Results of the Meta-Analysis
Compared with the control group, the supplementation of capsaicin resulted in significant reduction on BMI (WMD: −0·25 kg/m2, 95 % CI = -0·35, -0·15 kg/m2, P < 0·05), body weight (BW) (WMD: −0·51 kg, 95 % CI = -0·86, -0·15 kg, P < 0·05) and waist circumference (WC) (WMD: −1·12 cm, 95 % CI = -2·00, -0·24 cm, P < 0·05). The current meta-analysis suggests that capsaicin supplementation may have rather modest effects in reducing BMI, BW, and WC for overweight or obese individuals.
Capsaicin's Potential Mechanisms of Action
Evidence showed dietary chili has the potential to promote lipid oxidation, reduce appetite and accelerate energy metabolism, which may have a certain impact on weight loss. The mechanism of increasing lipid oxidation and energy consumption is due to the activation of transient receptor potential vanilloid subtype 1 (TRPV1) channels. Preclinical experiments have shown that capsaicin is a potent agonist of TRPV1. It is well accepted that the mechanism of action for this effect is caused by activation of the TRPV1 Ca channel, of which capsaicin is a potent antagonist. A 2009 study found that capsaicin increased the energy metabolism in wild-type mice but not in TRPV1 knockout mice. It seems TRPV1 activation causes the release of catecholamines, which stimulates the sympathetic nervous system via β-adrenoceptors. In another trial, the use of β-adrenergic blocker propranolol abolished the increase in thermogenesis in human subjects.
It has been found that the TRPV1 channel of adipose tissue is damaged when the human body is obese, but animal experiments show that long-term dietary capsaicin can significantly up-regulate the TRPV1 channel of adipose tissue and enhance its function, inhibit the related molecules of adipogenesis, and thus inhibit the occurrence of obese induced by high fat in mice. Interestingly, the effect on appetite, contrary to our perception that eating spicy food increases appetite, reduces appetite and increases satiety, but the mechanism of its effect on appetite is unclear. Acute lunches containing capsaicin have been shown to increase GLP-1 and tend to decrease auxin-releasing peptide, which may affect hunger.
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Neuromodulatory Mechanisms of TRPV1
Regulation of Feeding Behavior and Energy Metabolism by TRPV1 Activation in the Central Nervous System
The TRPV1 protein in the central nervous system (CNS) plays an important role in the regulation of feeding behavior. TRPV1-positive neurons are widely distributed in the CNS, especially in the hypothalamus and nucleus tractus solitarius (NTS), which are closely related to food intake and energy expenditure. TRPV1 expression in the hypothalamus of high-fat diet (HFD)-fed mice was significantly downregulated, whereas capsaicin restored its expression level, and activation of TRPV1 was able to increase energy expenditure and reduce body weight.
In the hypothalamus, TRPV1-positive neurons coexpress a variety of neuropeptides [including calcitonin gene-related peptide (CGRP), NPY, and substance P (SP)] to regulate peripheral thermogenesis and dietary intake. TRPV1 activation induces Ca2+ influx, which may be crucial for the release and function of CGRP, and CGRP may inhibit food intake by increasing cyclic adenosine monophosphate (cAMP) and cholecystokinin (CCK) expression in the hypothalamus, downregulating the expression of appetite-inducing neuropeptides (NPY and MCH), and increasing skin temperature and brown adipose tissue (BAT) thermogenesis. In POMC neurons, which regulate appetite and satiety, TRPV1 activation releases α-melanocyte-stimulating hormone (α-MSH) to act on satiety centers, leading to a reduction in appetite, and this process is TRPV1 dependent. In terms of hypothalamic gene expression profiles in HFD-fed mice, TRPV1 activation upregulates the expression of satiety-related neuropeptide genes (e.g., UCN, PYY, RAMP3, GRP, BDNF, and CARTPT) and downregulates the expression of appetite-stimulating genes (e.g., CNR1, GALR1, GHRL, ADRA2B, and GHSR), reducing food intake and body weight.
Central Regulation of Tissue Energy Metabolism is Dependent on Activation of TRPV1 in Peripheral Sensory Nerves
Peripheral sensory nerves are involved in regulating adipose tissue thermogenesis and WAT browning processes. Studies have shown that BAT-specific denervation in rats is associated with increased body weight; decreased resting metabolic rates; decreased BAT mass; decreased adipocyte and mitochondrial numbers; downregulated UCP1 protein expression; and decreased core body temperature. In contrast, both unilateral and bilateral ablation of subcutaneous WAT in mice upregulated the expression of thermogenic genes and was accompanied by beige adipocyte formation. These findings suggest that neuromodulation is necessary to maintain the homeostasis of fat energy metabolism.
The regulation of energy metabolism in adipose tissue is dependent on neuropeptide secretion following TRPV1 activation. Mammalian adipose tissue function is regulated by the peripheral nervous system, and the activation of TRPV1 in BAT and WAT sensory neurons results in the expression of the neuropeptides CGRP and SP, which transmit information from adipose tissue to the central nervous system (hypothalamus, solitary tract nucleus, etc.) through synaptic links between neurons, and the removal of sensory nerves of the adipose tissue results in compensatory hyperplasia, further demonstrating the involvement of sensory signaling in systemic adipose homeostasis. Thus, sympathetic and sensory nerves synergistically regulate fat metabolism through a bidirectional loop, with sympathetic nerves dominating lipolysis and thermogenesis and sensory nerves feeding back on fat status to modulate sympathetic output, a mechanism that is functionally specific in WAT and BAT but shares some central nodes.
In addition, the neuropeptides CGRP and SP released upon sensory nerve activation exert regulatory effects on adipose tissue metabolism. Previous studies have shown that CGRP has hormonal effects as a neuropeptide. Lipid metabolism regulation by CGRP may occur through changes in plasma catecholamine, cortisol, glucagon, insulin, lactate, and adipokine levels, as well as in the blood supply of adipose tissue. SP upregulates neurokinin 1 receptor (NK1R) mRNA and protein expression levels in human preadipocytes. SP also promotes lipolysis in 3T3L1 adipocytes, blocks insulin-mediated fatty acid uptake, and inhibits the accumulation of lipid droplets during differentiation.
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Endocrine Regulatory Mechanisms of TRPV1
Adipose Tissue TRPV1 Activation Promotes Mitochondrial Oxidation
Adipose tissue is an important part of the human body. Owing to its structure and function, it can be divided into WAT, which is responsible for storing fat, maintaining body temperature and regulating metabolism throughout the body, and BAT, which generates a large amount of heat energy through the catabolism and oxidation of lipids and helps to maintain body temperature.
Adipose tissue TRPV1 activation to promote mitochondrial energy metabolism is required for WAT browning. WAT browning has been used as a novel strategy to improve metabolic health, and WAT browning is able to inhibit energy intake-induced weight loss by triggering thermogenesis to promote energy expenditure. Upon the activation of WAT-expressed TRPV1, the intracellular Ca2+ concentration increases, and the activation of calmodulin kinase II (CaMKII) causes the phosphorylation of AMP protein kinase (AMPK), leading to the activation of sirtuin 1 (SIRT-1), which serves as a sensor of cellular metabolism and energy utilization, the activation of which leads to the deacetylation of PPARγ and PRDM-16, both of which promote WAT browning. With the activation of TRPV1, the expression of UCP-1 and bone morphogenetic protein 8B (BMP8B) is upregulated. UCP-1 is localized on the inner mitochondrial membrane, and when activated, it short-circuits the mitochondrial proton gradient, thus promoting thermogenesis. By increasing p38 MAPK/CREB signaling and adiponectin activity, BMP8B enhances the sensitivity of BAT to NE to promote energy expenditure.
Following the activation of TRPV1, the mRNA levels of hormone-sensitive lipase (HSL), carnitine palmitoyltransferase Ia (CPT-Ia), which is a rate-limiting enzyme in mitochondrial fatty acid oxidation, and uncoupling protein 2 (UCP2) are increased. This results in increased lipolysis in adipocytes and a reduction in the intracellular lipid content.
Pancreatic β-Cell TRPV1 Activation Regulates Pancreatic Function
The pancreas is an important visceral organ in the regulation of glucose metabolism, and insulin, an anabolic hormone, is synthesized and secreted by pancreatic beta cells. In peripheral tissues, insulin promotes glucose uptake in adipose tissue and inhibits lipolysis, promoting fat storage in adipocytes, and in the central nervous system, insulin acts as an appetite suppressant to decrease food intake and body weight.
TRPV1 activation in pancreatic β-cells increases insulin secretion. Previous studies have shown that TRPV1 affects pancreatic function and insulin secretion in both humans and animals, and the activation of TRPV1 expressed on pancreatic β-cells by calcium influx increases insulin secretion, a process that involves the regulation of protein kinase C alpha (PKC alpha) and cyclic adenosine monophosphate cAMP. In addition, TRPV1 is coexpressed with CGRP in pancreatic nerve fibers, and inhibition of TRPV1 signaling decreases CGRP secretion, thereby increasing insulin secretion. Insulin sensitizes TRPV1 in sensory nerve endings, and TRPV1-activated neurons regulate pancreatic β-cell function through the release of neuropeptides such as SP and CGRP, where an increase in CGRP secretion decreases insulin release from pancreatic β-cells.
TRPV1 Activation and Lipolysis
The prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation.
TRPV1 and Cx43 Co-Expression in Adipose Tissue
TRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric, and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ, and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. This study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo.
Experimental Evidence: Capsaicin, TRPV1, and Lipolysis
Immunofluorescence demonstrated specific staining for co-expressed TRPV1 and Cx43 in the cell-cell connecting portions in primary cultured human visceral adipocytes and visceral adipose tissues from both wild-type mice (WT) and humans.
Acute exposure to capsaicin, a TRPV1-specific agonist, stimulated an increase in the cytosolic free calcium concentration ([Ca2+]i) in cultured 3T3-L1 preadipocytes. TRPV1-elicited Cx43 gap-junction assay showed that response of Ca2+ to capsaicin was completely inhibited by 18α-GA in Cx43-expressing HeLa cells. The capsaicin-induced calcium increase could be inhibited by 18α-GA at a concentration of 100 μmol/L, whereas the maximum effect was obtained at 150 μmol/L in 3T3-L1 preadipocytes. These results suggest that functional TRPV1 and Cx43 exist in adipose tissues and cells, both in humans and mice.
Electroacupuncture and TRPV1
Acupuncture originated in ancient China at least 2,500 years ago. While treating obesity using acupuncture, it is essential to select the points based on differentiation of the symptoms and signs and multiple points in multiple meridians should be selected. The expression of TRPV1 in nerve fibers is significantly increased by EA stimulation in acupoints; moreover, the higher expression of TRPV1 in the subepidermal nerve fibers and its upregulation after EA stimulation may play a key role in mediating the transduction of EA signals to the central nervous system (CNS) and its expression in the subepidermal connective tissue cells may play a role in conducting the local effect of EA. Electroacupuncture (EA) reduces body weight in overweight subjects in clinical practice, as well as in rats and mice with diet-induced obesity.
EA and Body Weight Control: The Role of TRPV1
EA at ST36 acupoint attenuated body weight gain but not food and water intake. EA could reliably reduce the weight gain. Similar results were not observed if electrical stimulation was employed in non-acupoint gluteal maximus muscle (GM) area supporting an acupoint specificity. Importantly, EA cannot reduce body weight gain in TRPV1−/− mice suggesting a crucial target for EA manipulation.
EA at ST36 acupoint can decrease the body weight by attenuating WAT weight. The WAT weight decreased after 4 weeks of EA stimulation at ST36 acupoint. This pattern was not obtained in mice receiving sham-EA manipulation.
TRPV1 and Related Signaling Molecules in DRG and Spinal Cord
The protein level of TRPV1 was significantly increased after EA treatment. It was observed that the protein level of pPKA was increased in the EA-treated mice. Similar results were also obtained in the pPKC protein level suggesting its role in EA-mediated mechanisms. The results revealed that the protein level of pERK was significantly increased after EA treatment but not in the sham control mice.
TRPV1 was increased after EA treatment in spinal cord. The quantity of pPKA was increased after EA manipulation. Similar data were also observed in pPKC in the EA-treated group. These results also showed that pERK was drastically increased after EA treatment but not in the sham control.
TRPV1 Activation and BAT Thermogenesis
Increasing metabolism and thermogenesis in brown adipose tissue (BAT) can help in overcoming obesity. Dietary supplementation of capsaicin (TRPV1 agonist) on the expression of metabolically important thermogenic proteins in BAT of wild type and TRPV1−/− mice that received either a normal chow or high fat (± capsaicin; TRPV1 activator) diet by immunoblotting.
Capsaicin and BAT Activation
CAP antagonized high fat diet (HFD)-induced obesity without decreasing energy intake in mice. HFD suppressed TRPV1 expression and activity in BAT and CAP countered this effect. HFD feeding caused glucose intolerance, hypercholesterolemia and decreased the plasma concentration of glucagon like peptide-1 and CAP countered these effects. HFD suppressed the expression of metabolically important thermogenic genes, ucp-1, bmp8b, sirtuin 1, pgc-1α and prdm-16 in BAT and CAP prevented this effect.
The Role of SIRT-1
CAP increased the phosphorylation of sirtuin 1 and induced an interaction between PPARγ with PRDM-16. Further, CAP treatment, in vitro, decreased the acetylation of PRDM-16, which was antagonized by inhibition of TRPV1 by capsazepine, chelation of intracellular Ca2+ by cell permeable BAPTA-AM or the inhibition of SIRT-1 by EX 527. Further, CAP supplementation, post HFD, promoted weight loss and enhanced the respiratory exchange ratio. Data show that activation of TRPV1 in BAT enhances the expression of SIRT-1, which facilitates the deacetylation and interaction of PPARγ and PRDM-16.