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Dietary capsaicin and its anti-obesity potency: From mechanism to clinical implications


Abstract and Figures

Obesity is a growing public health problem, which has now been considered as a pandemic non-communicable disease. However, the efficacy of several approaches for weight loss is limited and variable. Thus, alternative anti-obesity treatments are urgently warranted, which should be effective, safe and widely available. Active compounds isolated from herbs are similar with the practice of Traditional Chinese Medicine, which has a holistic approach that can targets to several organs and tissues in the whole body. Capsaicin, a major active compound from chili peppers, has been clearly demonstrated for its numerous beneficial roles in health. In this review, we will focus on the a less highlighted aspect, in particular how dietary chili peppers and capsaicin consumption reduce body weight and its potential mechanisms of its anti-obesity effects. With the widespread pandemic of overweight and obesity, the development of more strategies for the treatment of obesity is urgent. Therefore, a better understanding of the role and mechanism of dietary capsaicin consumption and metabolic health can provide critical implications for the early prevention and treatment of obesity.
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Dietary capsaicin and its anti-obesity potency: From
mechanism to clinical implications
Jia Zheng1, Sheng Zheng2, Qianyun Feng2, Qian Zhang1, Xinhua Xiao1*
1Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health,
Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy
of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
2Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
*Corresponding author: Xinhua Xiao, E-mail:; Tel:
+86-10-69155073. No. 1 Shuaifuyuan, Wangfujing Street, Dongcheng District, Beijing
100730, P. R. China.
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Abstract: Obesity is a growing public health problem, which has now been considered as
a pandemic non-communicable disease. However, the efficacy of several approaches for
weight loss is limited and variable. Thus, alternative anti-obesity treatments are urgently
warranted, which should be effective, safe and widely available. Active compounds
isolated from herbs are similar with the practice of Traditional Chinese Medicine, which
has a holistic approach that can targets to several organs and tissues in the whole body.
Capsaicin, a major active compound from chili peppers, has been clearly demonstrated
for its numerous beneficial roles in health. In this review, we will focus on the a less
highlighted aspect, in particular how dietary chili peppers and capsaicin consumption
reduce body weight and its potential mechanisms of its anti-obesity effects. With the
widespread pandemic of overweight and obesity, the development of more strategies for
the treatment of obesity is urgent. Therefore, a better understanding of the role and
mechanism of dietary capsaicin consumption and metabolic health can provide critical
implications for the early prevention and treatment of obesity.
Keywords: Capsaicin; obesity; TRPV1; adipogenesis; brown adipose tissue; appetite
Abbreviations (alphabetically): BAT, brown adipose tissue; BMI, body mass index;
BMP8b, bone morphogenetic protein-8b; cAMP, cyclic adenosine monophosphate;
C/EBP-Į, CCAAT-enhancer-binding protein-Į; PKA, protein kinase A; GLP-1,
glucagon-like peptide-1; GPDH, glycerol-3-phosphate dehydrogenase; Muc2, mucin 2
gene; NF-țB, nuclear factor- kappa B; PPARĮ, peroxisome proliferator activated
receptor Į; PPARȖ, peroxisome proliferator activated receptor-Ȗ; PRDM-16, positive
regulatory domain containing 16; PGC1-Į, PPARȖ coactivator 1-Į; Reg3g, regenerating
islet-derived protein 3 gamma; SIRT-1, sirtuin-1; STAT-3, signal transducer and
activator of transcription-3; T2DM: type 2 diabetes mellitus; TRPV1, transient receptor
potential vanilloid 1; UCP-1, uncoupling protein 1; WAT, white adipose tissue˗WHO˖
World Health Organization.
1. Introduction
The epidemic of obesity is a growing public health problem. The incidence of obesity has
more than doubled since 1980, and has now reached worldwide epidemic status [1]. In
2014, the World Health Organization (WHO) estimated that 39% of the human adult
population with 1.9 billion people were affected with overweight (body mass index (BMI)
ı25 kg/m2), and that obesity (BMIı30 kg/m2) affected about 13% with 600 million
people [2, 3]. Obesity is a serious risk factor as it is associated with chronic inflammation
and metabolic syndrome [4], a cluster of morbidities that includes hypertension,
hyperlipidemia and type 2 diabetes mellitus (T2DM) [5]. It can increase the risks of
developing serious health problems, such as cardiovascular diseases, chronic kidney
disease and stroke [6, 7]. Moreover, obese patients are more prone to contract several
forms of cancer with reduced chances of survival [8]. Of particular concern is the
incidence of overweight and obesity in children, with an estimated one-third of children
and adolescents affected in the United States and over 41 million children are overweight
before reaching puberty [2]. As such, obesity and its related diseases yield enormous tolls
at individual, public health and economic levels. In addition, genome-wide association
studies (GWAS) have revealed compelling genetic signals influencing obesity risk and
genetic polymorphism plays a major role in determining obesity [9]. An updated
randomized controlled trial indicated that greater body weight and waist circumference
reductions in risk carriers than in nonrisk carriers of the fat-mass and obesity-associated
(FTO) geneacross different levels of personalized nutrition [10]. These data signify that
the interventions should be personalized and varies with each individual [11]. Thus, the
development of novel and personalized strategies for the early prevention and treatment
of overweight and obesity is warrant.
2. Limitations in anti-obesity approaches
It has clearly established that weight loss will significantly diminish the complications of
obesity [12]. Emerging human epidemiology studies indicated that reducing body weight,
with weight loss of at least 5%, has long-term benefits on metabolic health and reduces
the risks of developing insulin resistance, T2DM and cardiovascular diseases [13].
However, weight loss is difficult and the obese individuals are struggling to achieve it
and the efficacy of several approaches for weight loss is limited and variable [14, 15].
Firstly, it is widely accepted that a combination of physical exercise and low calorie diet
is the best approach to prevent and treat obesity. However, this strategy is difficult to
implement and its compliance is poor. Gupta et al. aimed to explored treatment
satisfaction associated with different weight loss methods among patients with obesity. It
showed that using self-modification weight loss techniques, such as, diet, exercise and
weight loss supplements has lowest treatment satisfaction, compared with gastric bypass
and gastric banding, and prescription medication [16]. In addition, physical exercise and
diet intervention also yield enormous tolls at economic level. It reported that retail sales
of weight-loss supplements were estimated to be more than $1.3 billion in 2001 in US
[17]. Thus, cheap, easily available therapies and supplements are urgently needed. The
second approach is pharmaceutical drugs, such as Orlistat, a potent and specific inhibitor
of intestinal lipases. It can reduce body weight with an average weight loss of 3% during
one year period [13]. However, its efficacy is variable and it can lead to gastrointestinal
adverse effects, liver failure and acute kidney injury [18]. Other anti-obesity drugs, such
as rimonabant, fenfluraminea and sibutramine, have been withdrawn from the market due
to severe adverse effects, including increased cardiovascular risks, mood disorders and
even suicidal susceptibility [14]. Thirdly, anti-diabetic agents, such as, glucagon-like
peptide 1 (GLP-1) analogue, liraglutide has been shown its potential anti-obesity efficacy
[19]. But it needs to be injected subcutaneously daily. Moreover, the weight loss is
limited and it can increase the risk of pancreatitis [20]. Compared with aforementioned
anti-obesity drugs, bariatric surgery such as Roux-en-Y gastric bypass or sleeve
gastrectomy is more effective. However, it is physically invasive, relatively expensive
and its long-term effect is unclear [21]. Therefore, alternative anti-obesity treatments are
urgently warranted, which should be effective, safe and widely available.
3. An overview of chili peppers and capsaicin
Chili pepper is generally used as a flavoring spice and is prominent in diets of various
communities and cultures worldwide since 7000BC, with a long history of flavoring,
coloring, preserving food as well as medication [26]. In chili pepper, more than 200
active constituents have been identified and some of its active constituents play multiple
roles in the whole body [27]. Capsaicin, as a major active compound from chili pepper,
has been established for its numerous beneficial roles in the human organism, including
the treatment of pain inflammation, rheumatoid arthritis [28] and vasomotor rhinitis [29]
(Figure 1). Furthermore, capsaicin has proven an effective anti-cancer agent. Several
preclinical studies showed that capsaicin could suppress various human neoplasia by
generating reactive oxygen species and increasing apoptosis [30, 31]. Finally, capsaicin
demonstrated significant antioxidant properties and it was postulated that this compound
has important implications in the prevention or treatment of neurodegenerative diseases
such as Alzheimer’s disease [32]. In addition tocapsaicin as anti-obesity compounds,
other types of natural products also have shown to be considered as anti-obesity
compounds. Celastrol (from roots of the thunder god vine) can reduce appetite and food
intake in mice that are fed a high-fat diet [33]. Stilbenoid resveratrol (from grapes and red
wine), genistein (an isoflavone from soy), glycyrrhizin (from liquorice), quercetin,
ethanolic extract (from ginseng roots) and green tea extract (including camellia sinensis,
catechin, caffeine, and epigallocatechin gallate), play a role in adipogenesis inhibition,
thus may have anti-obesity potency [15]. In this review, we will focuses on the a less
highlighted aspect, in particular how dietary chili peppers and capsaicin consumption
reduce body weight and its potential mechanisms of its anti-obesity effects. Figure 1
shows the molecular structure of capsaicin and isolated from chili peppers.
4. Clinical studies of the weight-loss effects of capsaicin
4.1 Weight-loss effects of capsaicin on lipid oxidation and energy expenditure
Epidemiological data revealed that the consumption of foods containing capsaicin was
associated with a lower prevalence of obesity [34]. In one double-blind, randomized,
placebo controlled trial, it indicated that treatment of overweight or obese subjects with 6
mg/d capsinoid for 12 weeks was associated with abdominal fat loss measured by dual
energy X-ray absorptiometry. Body weight was decreased as 0.9 and 0.5 kg in the
capsinoid and placebo groups, respectively. Moreover, none of the patients developed any
adverse events [35] (Table 1). Lejeune et al. aimed to investigate whether capsaicin
assists weight maintenance by limiting weight regain after weight loss of 5% to 10%. The
results showed that capsaicin treatment caused sustained fat oxidation during weight
maintenance compared with placebo [36] (Table 1). Increase the oxygen consumption
(VO2) and body temperature, reflecting increased energy expenditure, thus play critical
role in weight loss. Fat oxidation was reported to be sustained together with elevation of
the resting energy expenditure and enhanced fat oxidation may contribute to increased
energy expenditure. In another randomized double-blind study, it indicated that subjects
between 30 and 65-year old with a BMI >23 kg/m2 treated with capsinoid (10 mg/kg per
day) for 4 weeks safely and body weight tended to decrease during the 2 to 4 week period,
with increased VO2, resting energy expenditure, fat oxidation significantly [37] (Table 1).
Enhanced lipid oxidation and increased energy expenditure are potentially beneficial for
weight management [38].
4.2 Weight-loss effects of capsaicin on appetite and brown adipose tissue
Dietary red pepper can suppress energy intake and modify macronutrient intake through
appetite and satiety regulation [39]. One prospective study aimed to investigate the
effects of capsaicin on feeding behavior and energy intake. It indicated that the addition
of red pepper to the breakfast significantly decreased protein and fat intakes at lunch time
and the addition of red pepper to the appetizer significantly reduced the cumulative ad
libitum energy and carbohydrate intakes during the rest of the lunch. These effects might
be related to an increase in sympathetic nervous system activity [40] (Table 1). Brown
adipose tissue (BAT) is known to play a critical role in cold-induced non-shivering
thermogenesis to maintain body temperature and it is expected to be a therapeutic target
for obesity and related metabolic disorders in humans [41]. It showed Chili pepper affects
energy expenditure by triggering the BAT in the same way as low temperature does,
leading to increased energy expenditure via non-shivering thermogenesis [42]. One recent
clinical study showed that 9 mg of capsinoid for 8 weeks could increase BAT activity and
increase thermogenesis in healthy subjects [43] (Table 1). The results suggest dietary
capsaicin consumption could have a beneficial effect for weight management, by
reducing energy intake and activation of brown adipose tissue activity. The summary of
the clinical studies about the weight-loss effects of capsaicin was shown Table 1.
5. Pre-clinical studies aboutanti-obesity effects of capsaicin and its potential
5.1 Capsaicin and TRPV1 activation
Numerous epidemiology studies and animal studies indicated that capsaicin, as a transient
receptor potential vanilloid 1 (TRPV1) agonist, it may represent a potential strategy to
treat obesity. Although it is well accepted much of the effect is caused by stimulation of
the TRPV1 receptor, the mechanism of action is not presently fully understood.
Increasing evidence indicates that TRPV1 plays a critical role in the regulation of
metabolic health for the whole body, including body weight, glucose and lipid
metabolism, and cardiovascular system [44, 45]. TRPV1 was deemed as a potential target
for the prevention of obesity due to its effect on energy metabolism and balance [46, 47].
Activation of TRPV1 by capsaicin can attenuate abnormal glucose homeostasis by
stimulating insulin secretion and increasing glucagon-like peptide-1 (GLP-1) levels [48,
49] (Table 2). Furthermore, capsaicin also plays its role in a receptor-independent manner.
It reported that capsaicin was associated with nuclear factor-kappa B (NF-țB)
inactivation and peroxisome proliferator activated receptor-Ȗ (PPARȖ) activation, and
then it could modulate adipocyte function of adipose tissues in obese-mouse and
suppressed the inflammatory responses of adipose tissue macrophages, which is
independent on TRPV1 [50]. Additionally, TRPV1 can play a critical role in cell
proliferation and cancer. It showed that TRPV1 implicated as a regulator of growth factor
signaling in the intestinal epithelium, which could subsequent suppress intestinal
tumorgenesis [51].
The potential mechanisms underlying the anti-obesity effects of capsaicin include: (1)
increase lipid oxidation and inhibit adipogenesis; (2) activate brown adipose tissue (BAT)
activity and induce thermogenesis; (3)suppress appetite and increase satiety regulated by
neuronal circuits in the hypothalamus; (4) modulate the function of gastrointestinal tract
and gut microbiome. The molecular mechanisms of the anti-obesity effects of capsaicin
were summarized in Figure 2. In addition, we further collected most pre-clinical studies,
including in-vitro studies and rodent experiments about the anti-obesity effects of
capsaicin (shown in Table 2).
5.2 Capsaicin and its role in adipogenesis
Adipogenesis is the critical and original process of fatty adipose accumulation. It
suggested that decreased preadipocyte differentiation, proliferation and lipogenesis have
the potential to reduce obesity. Hsu et al. demonstrated that capsaicin inhibited the
expression of PPARȖ, CCAAT-enhancer-binding protein-Į (C/EBP-Į) and leptin, but
induced up-regulation of adiponectin at the protein level. Thus, it efficiently induced
apoptosis and inhibits adipogenesis in 3T3-L1 preadipocytes and adipocytes in vitro [52]
(Table 2, Figure 2). Zhang et al. found that capsaicin treatment prevented adipogenesis of
3T3-L1-preadipocytes in vitro, with increased intracellular calcium [53] (Figure 2). Male
C57BL/6 obese mice fed a high-fat diet for 10 weeks received a supplement of 0.015%
capsaicin showed decreased fasting glucose, insulin, leptin concentrations, and markedly
improved glucose intolerance in obese mice, accompanied with decreased TRPV-1
expression in adipose tissue, increased adiponectin expression in the adipose tissue and
increased peroxisome proliferator activated receptor Į (PPARĮ) and PPARȖ coactivator
1-Į (PGC-1Į) expression in the liver [54] (Table 2, Figure 2). Ohnuki et al. demonstrated
that mice treated with 10 mg/kg body weight capsaicin could markedly suppressed body
fat accumulation and promoted energy metabolism [55] (Table 2). Hence, these studies
supported that capsaicin could decrease adipogenensis and regulate genes function related
with lipid metabolism, and then it can has the potential to lose weight.
5.3 Capsaicin and its role in brown adipose tissue
BAT is the main site of adaptive thermogenesis and experimental studies have associated
BAT activity with protection against obesity and metabolic diseases [56]. A review
illustrated that the activity of BAT can be activated and recruited not only by cold
exposure but also by various food ingredients, such as capsaicin in chili pepper [57]
(Table 2). Capsinoids supplementation with exercise in C57BL/6J mice additively
decreased body weight gain and fat accumulation, and increased whole body energy
expenditure compared with exercise alone. The underlying mechanisms may be
associated with increased energy expenditure, lipolysis activation in BAT and increased
cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in
BAT [58] (Table 2, Figure 2). One up-to-date rodent experiment showed that capsaicin
could counter the detrimental effects of high-fat diet, including glucose intolerance,
hypercholesterolemia and suppressed activity in BAT. These effects were mainly by
increasing the expression of metabolically important thermogenic genes, including
uncoupling protein 1 (UCP-1), bone morphogenetic protein-8b (BMP8b), sirtuin-1
(SIRT-1), PGC-1Į and PR domain containing zinc finger protein 16 (PRDM-16) in BAT.
Furthermore, capsaicin supplementation, post high-fat diet, promoted weight loss and
enhanced the respiratory exchange ratio. All these data suggested that capsaicin is a novel
strategy to counter diet-induced obesity by enhancing metabolism and energy expenditure
[59] (Table 2, Figure 2). Baskaran et al. showed that activation of TRPV1 channels by
dietary capsaicin triggered browning of adipose tissue to counteract obesity [60] (Table 2).
Collectively, these observations provide evidence that capsaicin can activate and recruit
BAT, which would be a promising strategy to counter obesity.
5.4 Capsaicin and its role in appetite and satiety
Energy balance requires an ability of the brain to detect the status of energy stores and
match energy intake with expenditure, and energy homeostasis is mainly controlled by
neuronal circuits in the hypothalamus [61]. Hypothalamic endoplasmic reticulum stress
occurs in individuals with obesity and is thought to induce low levels of leptin receptor
signaling and play a central role in development of leptin resistance [62]. The adipose
tissue-derived hormone leptin acts via its receptor in the brain to regulate energy balance
and neuroendocrine function. Leptin resistance is a pathological condition, which means
the lack of appetite reduction in response to leptin and the body fails to adequately
respond to it [63]. Lee et al. found that TRPV1 had a major role in regulating glucose
metabolism and hypothalamic leptin's effects in obesity, with hypothalamic signal
transducer and activator of transcription-3 (STAT-3) activity blunted in the TRPV1 knock
out mice [64] (Figure 2). Addition of dietary capsaicin has been shown to increase satiety
and it indicated that capsaicin increased sensation of fullness in energy balance, and
decreased desire to eat after dinner in negative energy balance [65]. Although the studies
about capsaicin and its role in appetite is limited, it inspired us that neuronal circuits in
the hypothalamus may be a pivotal target of capsaicin.
5.5 Capsaicin and its role in gastrointestinal tract and gut microbiome
Capsaicin is passively absorbed in the stomach with greater than 80% efficiency and
upper portion of the small intestine [66]. Thus, it may activate local TRPV1 channels in
gastrointestinal tract to initiate a series of physiological effects. Dietary capsaicin
consumption triggered the intestinal mucosal afferent nerves and increased intestinal
blood flow [67]. Acute single administration of 640 umol/L capsaicin into the duodenal
lumen in anesthetized rats significantly increases superior mesenteric artery blood flow
[68] (Table 2). In addition, it showed that dietary capsaicin ameliorated abnormal glucose
homeostasis and increased GLP-1 levels in the plasma and ileum through the activation
of TRPV1-mediated GLP-1 secretion in the intestinal cells and tissues [49] (Table 2,
Figure 2). Recent study demonstrated that anti-obesity effect of capsaicin in mice fed
with high-fat diet was associated with an increase in population of the gut bacterium
Akkermansia muciniphila. Further studies found that capsaicin directly up-regulated the
expression of Mucin 2 gene Muc2 and antimicrobial protein gene regenerating
islet-derived protein 3 gamma (Reg3g) in the intestine[69] (Table 2, Figure 2). These data
suggested that the anti-obesity effect of capsaicin is associated with a modest modulation
of the function in gastrointestinal tract and gut microbiome.
6. Conclusion
In summary, capsaicin plays a critical role in human and has multiple benefits for
metabolic health, especially for weight loss in obese individuals. It is well accepted that
the potential application of active compounds isolated from herbs are similar with the
practice of traditional Chinese medicine, which has a holistic approach that can targets to
different organs and tissues in the whole body. More importantly, no adverse effects with
capsaicin were observed in most studies. Thus, chili peppers and capsaicin are safely and
easily applicable to our daily life. Considering that chili peppers have been a vital part of
culinary cultures worldwide and have a long history of use for flavoring, so it is more
feasible to be utilized to treat overweight and obesity, compare with medications or other
interventionswith certain side effects. Dietary chili peppers supplementation or to be
food additives, with ideal dosage may be tentative methods for capsaicin to play its
protective roles in metabolic health. With the widespread pandemic of overweight and
obesity, the development of more strategies for the treatment of obesity is urgent.
Therefore, a better understanding of the role and mechanism of dietary capsaicin
consumption and metabolic health can provide critical implications for the early
prevention and treatment of obesity.
Competing Interest: The authors declare that there are no competing interests associated
with the manuscript.
Acknowledgments: This work was supported by the National Natural Science
Foundation of China (No. 81170736, 81570715), National Key Research and
Development Program of China (No. 2016YFA0101002) and National Natural Science
Foundation for Young Scholars of China (No. 81300649) and China Scholarship Council
Foundation (No. 201506210378). The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Author Contribution: J.Z. and X.H.X. have made substantial contributions to ideas,
conception and design of the review. S.Z. and Q.Y.F. searched the databases, selected
studies, extracted the data and wrote the manuscript. S.Z. and Q.Z. reviewed and edited
the manuscript. X.H.X. contributed to the design and reviewed and edited the manuscript.
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Figure Legends
Figure 1. The molecular structure of capsaicin and isolated from chili peppers.
Figure 2. Molecular mechanisms of the anti-obesity effects of capsaicin. A. Capsaicin
can inhibit adipogenesis in preadipocyte and adipocyte by up-regulating the expression of
PPARȖ and UCP-1. Thus, it will increase stimulate adiponectin secretion and increase
body fat accumulation; B. Capsaicin can activate BAT activity, accompanied by increased
expression of UCP-1 and PGC1-; C.Capsaicin can suppress appetite, increase satiety and
ameliorate insulin resistance; D. Capsaicin can modulate its function in gastrointestinal
tract and gut microbiome, including stimulate GLP-1 secretion and increase in population
of the gut bacterium Akkermansia muciniphila. BAT: brown adipose tissue; GLP-1:
glucagon-like peptide-1; Muc2: mucin 2 gene; PPARĮ: peroxisome proliferator activated
receptor Į; PPARȖ: peroxisome proliferator activated receptor Ȗ; PGC1-Į: PPARȖ
coactivator 1-Į; Reg3g: regenerating islet-derived protein 3 gamma; STAT-3: signal
transducer and activator of transcription-3; TRPV1: transient receptor potential vanilloid
1; UCP-1: uncoupling protein 1; WAT: white adipose tissue.
Table 1 | Clinical studies of the weight-loss effects of capsaicin
Treatments Year Country Study design Subjects
Outcomes Adverse
(6 mg per
day for 12
2009 USA Double-blind,
30.6±2.4 N=80 42±8 Body weight
decreased 0.92
kg; Abdominal
fat decreased
None Increase in fat
oxidation and
Snitker et
al [35].
Red pepper
10 g single
1999 Canada Prospective study Healthy
25.3±4.7 N=23 25.8±2.8 Decreases
None Increase in
nervous system
et al [40].
(10 mg/kg
per day for
4 weeks)
2007 Japan Double-blind,
Men and
˚23 N=48 30–65 Body weight
tended to
decrease during
the 2 to 4 week
None Increased VO2,
and fat
Inoue et al
(135 mg per
day for 3
2003 Netherlands Randomized
29.3±2.5 N=140 18-60 Significant
increase in
resting energy
None More sustained
fat oxidation
Lejeune et
al [36].
(9 mg per
day for 8
2016 Japan Randomized
College students
N=20 20.7±1.2 Increased
None Increased
et al [43].
Table 2 | Pre-clinical studies aboutanti-obesity effects of capsaicin
Treatments Species Duration Metabolic disorders Potential Mechanism Reference
0-250 umol/L
preadipocytes and
24-72 hour - decreased the amount of
intracellular triglycerides, GPDH
- induced apoptosis;
- inhibited adipogenesis;
- inhibited the expression of PPARȖ,
C/EBP-Į, and leptin;
- induced up-regulation of adiponectin
at the protein level;
Hsu et al [52].
1 umol/L Capsaicin 3T3-L1-preadipo
3-8 days - prevented the adipogenesis - increased intracellular calcium Zhang et al
0.015% Capsaicin Male C57BL/6
10 weeks - decreased triglyceride levels;
- lowered fasting glucose, insulin,
leptin levels;
- decreased TRPV-1 expression in
adipose tissue;
- increased mRNA/protein of
adiponectin in the adipose tissue;
- increased PPARĮ/PGC-1Į mRNA in
the liver;
Kang et al [54].
10 mg/kg-body
weight Capsaicin
Std ddY mice 2 weeks - lower body weight;
- markedly suppressed body fat
- decreased triglyceride levels;
- increased oxygen consumption;
- stimulated the secretion of adrenalin;
Ohnuki et al
0.3% Capsinoids C57BL/6J mice 8 weeks - suppressed body weight gain under
the HFD;
- decreased plasma cholesterol level;
- prevented diet-induced liver
- increased energy expenditure;
- activation of fat oxidation in skeletal
- activation lipolysis in BAT;
- increased cAMP levels and PKA
activity in BAT;
Ohyama et al
[57, 58].
0.003%, 0.01% and
0.03% Capsaicin
wild-type and
TRPV1í/í mice
16 weeks - promoted weight loss;
- enhanced the respiratory exchange
- countered hypercholesterolemia;
- increased the expression UCP-1,
BMP8b, SIRT-1, PGC-1Į and
prdm-16 in BAT;
- increased the phosphorylation of
Baskaran et al
0.01% Capsaicin wild-type and
TRPV1í/í mice
26 weeks - countered obesity;
- browning of WAT;
- promoted sirtuin-1 expression;
- increased the expression of PGC-1Į;
- facilitated PPARȖ-PRDM-16
Baskaran et al
0.01% Capsaicin wild-type and
TRPV1í/í mice
24 weeks - ameliorated abnormal glucose
- increased GLP-1 levels in the
plasma and ileum;
- activation of TRPV1-mediated GLP-1
secretion in the intestinal cells;
Wang et al
640 umol/L, 2 ml/kg
15min - increased superior mesenteric artery
blood flow;
- reduction in hydrogen gas
- induced a dichotomous pattern of
blood flow changes;
Leung et al
0.01% Capsaicin C57BL/6J male
9 weeks - reduced weight gain;
- improved glucose tolerance;
- modest modulation of the gut
- up-regulated the expression of Mucin
2 gene and antimicrobial protein gene
Reg3g in the intestine;
Shen et al [69].
BAT, brown adipose tissue; BMP8b, bone morphogenetic protein-8b; cAMP, cyclic adenosine monophosphate; C/EBP-Į, CCAAT-enhancer-binding protein-Į;
PKA, protein kinase A; GLP-1, glucagon-like peptide-1; GPDH, glycerol-3-phosphate dehydrogenase; PPARĮ, peroxisome proliferator activated receptor Į;
PPARȖ, peroxisome proliferator activated receptor-Ȗ; PRDM-16, positive regulatory domain containing 16; PGC1-Į, PPARȖ coactivator 1-Į; SIRT-1, sirtuin-1;
TRPV1, transient receptor potential vanilloid 1; UCP-1, uncoupling protein 1; WAT, white adipose tissue.
... Mice that followed a diet containing 0.0014% Capsaicin without any caloric change obtained a reduction in body weight, particularly related to visceral fat loss [80]. Different research studies confirmed that Capsaicin can suppress obesity-induced inflammation by regulating adipokine production in obese mice [73]. ...
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... Bioactive compounds from pepper are known for their analgesic, cardioprotective, pharmacological, neurological, and antiobesity properties [25]. Capsaicin, as a major active compound from pepper, has numerous beneficial roles in humans [15]. Dietary capsaicin consumption could have a beneficial effect on weight management by activating brown adipose tissue activity and reducing energy intake via appetite and satiety regulation [26]. ...
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The habanero pepper (Capsicum chinense) is an increasingly important spice and vegetable crop worldwide because of its high capsaicin content and pungent flavor. Diets supplemented with the phytochemicals found in habanero peppers might cause shifts in an organism’s metabolism and gene expression. Thus, understanding how these interactions occur can reveal the potential health effects associated with such changes. We performed transcriptomic and metabolomic analyses of Drosophila melanogaster adult flies reared on a habanero pepper diet. We found 539 genes/59 metabolites that were differentially expressed/accumulated in flies fed a pepper versus control diet. Transcriptome results indicated that olfactory sensitivity and behavioral responses to the pepper diet were mediated by olfactory and nutrient-related genes including gustatory receptors (Gr63a, Gr66a, and Gr89a), odorant receptors (Or23a, Or59a, Or82a, and Orco), and odorant-binding proteins (Obp28a, Obp83a, Obp83b, Obp93a, and Obp99a). Metabolome analysis revealed that campesterol, sitosterol, and sucrose were highly upregulated and azelaic acid, ethyl phosphoric acid, and citric acid were the major metabolites downregulated in response to the habanero pepper diet. Further investigation by integration analysis between transcriptome and metabolome data at gene pathway levels revealed six unique enriched pathways, including phenylalanine metabolism; insect hormone biosynthesis; pyrimidine metabolism; glyoxylate, and dicarboxylate metabolism; glycine, serine, threonine metabolism; and glycerolipid metabolism. In view of the transcriptome and metabolome findings, our comprehensive analysis of the response to a pepper diet in Drosophila have implications for exploring the molecular mechanism of pepper consumption.
... It triggers the activation of the TRPV1 mechanism that can reduce abnormal glucose homeostasis by promoting the release of insulin and increasing the levels of glucagon-like peptide-1 (GLP-1). It promotes lipid oxidation, inhibits adipogenesis, activates thermogenesis, decreases appetite, and increases satiety, controlled by neuronal circuits in the hypothalamus [103]. In addition to inhibiting the expression of PPAR-γ, C/EBP-α, and leptin, capsaicin dramatically reduced the glycerol-3-phosphate dehydrogenase (GDPH) activity and intracellular triglyceride in 3T3-L1 adipocytes [104]. ...
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... Accumulating evidence has indicated that capsaicin has excellent anti-obesity activity by facilitating fat oxidation and energy expenditure, improving insulin sensitivity, and promoting the white adipose browning in both rodents and adult humans [126][127][128]. However, there are several disadvantages of capsaicin limiting its application as oral supplements, including poor water solubility, low bioavailability, and obvious irritation of the mouth and gastrointestinal tract [129]. Bao et al. successfully developed a nanomedicine by using α-lactalbumin (α-lac) nanomicelles to encapsulate capsaicin and then delivered it directly to adipose tissues by a microneedle technology [89]. ...
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... STAT-3, and signal transducer and activator of transcription-3 (STAT3). Reproduced with permission from[66]. ...
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Medical management of obesity represents a large unmet clinical need. Animal experiments suggest a therapeutic potential for dietary capsaicin, the pungent ingredient in hot chili peppers, to lose weight. This is an attractive theory since capsaicin has been a culinary staple for thousands of years and is generally deemed safe when consumed in hedonically acceptable, restaurant-like doses. This review critically evaluates the available experimental and clinical evidence for and against capsaicin as a weight control agent and comes to the conclusion that capsaicin is not a magic “exercise in a pill”, although there is emerging evidence that it may help restore a healthy gut microbiota.
... In addition, its effects have been studied in obesity. Capsaicin acts on metabolism, increasing thermogenesis and contributing to the reduction in fat, especially visceral fat [313,314]. Furthermore, capsinoids, the secondary metabolites of capsaicin, increase the feeling of satiety [314,315]. Capsaicin can contribute to the treatment of pain not only for its analgesic properties but also for inhibiting the expression of inflammatory cytokines, thus counteracting the effects of many chronic inflammatory and autoimmune diseases [312,316]. ...
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... These products have several applications including dietary supplements, medications, pain relievers, sprays for repelling animals, and personal defense (Rouhi, 1996). Their biological and physiological activities confer antioxidant (Materska and Perucka, 2005), anticancer (Macho et al., 2003), energy synthetic, fat mobilisation (Ohnuki et al., 2001;Zheng et al., 2017), and anti-inflammatory activities (Sancho et al., 2002). They also improve metabolic syndrome (Panchal et al., 2018), and possess antimicrobial properties mediated by microbiota alteration (Rosca et al., 2020). ...
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Capsaicinoids are a class of compounds that confer various pungency levels to peppers, and have a range of applications as dietary supplements, medications, pain relievers, and sprays for repelling animals and personal attackers. Although analyses and classifications of peppers have been extensively reported in the literature, data describing and classifying the pungency of Brazilian pepper sauces are scarce. The objective of the present work was therefore to measure the levels of nordihydrocapsaicin, capsaicin, and dihydrocapsaicin in commercial pepper sauce samples, classify their pungency, and compare them with the recommended daily intake limits. Solvent extraction was performed using ethanol, and capsaicinoids were identified and quantified using high-performance liquid chromatography (HPLC). Most of the samples had mild to moderate pungency expressed in Scoville Heat Units (SHU). There were no significant differences between sauces with and without milk on the pungency of green or red pepper sauces. Capsaicin levels were below the recommended daily intake limits. The capsaicin levels found in all but two of the pepper sauces were below the recommended limits for capsaicin daily intake in industrial foods samples. According to the United States Department of Agriculture (USDA) specifications, the classification of pungency is not a valid criterion for classifying pepper sauces; therefore, a new classification was proposed.
... Accumulating evidence has suggested that prolonged administration of either Capsaicin or Capsinoids, nonpungent Capsaicin analogues, for several weeks resulted in beneficial effects on fat oxidation, energy expenditure, insulin sensitivity, and body fat mass in both rodents and adult humans [14][15][16][17] . Although the mechanism of action of Capsaicin involves multiple tissues, its anti-obesity effects are mediated by the activation of the sympathetic nervous system via TRPV1 on sensory neurons [18][19][20][21][22] . Norepinephrine (NE) secreted at the end of sympathetic nerves increases cellular levels of cAMP via β-adrenergic receptors, which overlaps with cold-induced thermogenesis pathway. ...
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Human brown fat is a potential therapeutic target for preventing obesity and related metabolic diseases by dissipating energy as heat through uncoupling protein 1 (UCP1). We have previously reported a method to obtain chemical compound-induced brown adipocytes (ciBAs) converted from human dermal fibroblasts under serum-free conditions. However, pharmacological responses to bioactive molecules have been poorly characterised in ciBAs. This study showed that the treatment with Capsaicin, an agonist of transient receptor potential vanilloid 1, directly activated adipocyte browning such as UCP1 expression, mitochondrial biogenesis, energy consumption rates, and glycerol recycling in ciBAs. Furthermore, genome-wide transcriptome analysis indicated that Capsaicin activated a broad range of metabolic genes including glycerol kinase and glycerol 3-phosphate dehydrogenase 1, which could be associated with the activation of glycerol recycling and triglyceride synthesis. Capsaicin also activated UCP1 expression in immortalised human brown adipocytes but inhibited its expression in mesenchymal stem cell-derived adipocytes. Altogether, ciBAs successfully reflected the direct effects of Capsaicin on adipocyte browning. These findings suggested that ciBAs could serve as a promising cell model for screening of small molecules and dietary bioactive compounds targeting human brown adipocytes.
Capsaicin (CAP) rich diets may help with a variety of human pathophysiological conditions; however, CAP administration is difficult due to its high pungency and limited water solubility. This study comprehensively explored the mechanism of CAP binding with ovalbumin (OVA) and casein (CAS) by multi-spectroscopic, thermodynamics, and molecular docking simulation at pH 7.4, as well as the prospect of employing these food proteins as CAP carriers. The findings demonstrated that CAP could interact with OVA/CAS and increase their fluorescence intensity, which was followed by specific protein conformational changes. According to the ITC data, the interaction between CAP and OVA/CAS proceeded spontaneously, with hydrogen bonding and hydrophobic interactions governing the binding process. The binding constant Ka for the CAP-OVA and CAP-CAS complexes was determined by ITC to be 1.07 ± 0.21 ⅹ 10⁵ M⁻¹ and 2.22 ± 0.14 ⅹ 10⁵ M⁻¹, respectively. Molecular docking analysis further indicated the existence of a high affinity CAP binding site on OVA and CAS, supporting the experimental findings. Moreover, the data demonstrated that CAP binding interactions with these proteins led to the formation of complexes with about 97% CAP encapsulation efficiency, contributing to a synergistic enhancement in their antioxidant activity. Therefore, this study implies that OVA and CAS have great potential for being utilized as edible delivery vehicles for lipophilic bioactive molecules such as CAP.
Chili pepper and its major active compound capsaicin have long been used not only a daily food additive but also medication worldwide. Like in other human organs and systems, capsaicin has multiple actions in gastrointestinal (GI) physiology and pathology. Numerous studies have revealed that capsaicin acts on GI tract in TRPV1-dependent and –independent manners, mostly depending on its consumption concentrations. In this review, we will focus on the beneficial role of capsaicin in GI tract, a less highlighted aspect, in particular how dietary capsaicin affects GI health, the mechanisms of actions and its preventive/therapeutic potentials to several GI diseases. Dietary capsaicin affects GI tract not only via TRPV1-derpendent and independent manners, but also via acute and chronic effects. Although high dose intake of dietary capsaicin is harmful to human health sometimes, current literatures suggest that appropriate dose intake is likely beneficial to GI health and is preventive/therapeutic to GI disease in most cases as well. With extensive and intensive studies on its GI actions, capsaicin, as a daily consumed food additive, has potential to become a safe drug for the treatment of several GI diseases.
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This review aimed to summarize the evidence on the effectiveness of obesity prevention and treatment programmes for adolescents from socioeconomically disadvantaged backgrounds. A secondary aim was to identify potential successful intervention strategies for this target group. PubMed, EMBASE, PsycINFO and Cochrane Library were searched from January 2000 up to February 2016. Intervention studies targeting adolescents from disadvantaged backgrounds were included, with body mass index as outcome. Secondary outcomes were other adiposity measures, physical activity, diet, sedentary behaviour and screen time. Two independent reviewers extracted data, coded intervention strategies and conducted quality assessments. Fourteen studies were included: nine obesity prevention and five obesity treatment studies. Two preventive and four treatment studies showed significant beneficial effects on body mass index. Five of six studies (four preventive, one treatment studies) measuring dietary behaviour reported significant intervention effects. Evidence on other secondary outcomes was inconclusive. We found no conclusive evidence for which specific intervention strategies were particularly successful in preventing or treating obesity among disadvantaged adolescents. However, the current evidence suggests that involving adolescents in the development and delivering of interventions, the use of experiential activities and involvement of parents seem to be promising strategies. More high quality studies are needed. PROSPERO registration number: CRD42016041612.
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Capsaicin (CAP) reduces body weight mainly through activation of transient receptor potential vanilloid 1 (TRPV1) cation channel. However, recent evidence indicates that the gut microbiota influences many physiological processes in host and might provoke obesity. This study determined whether the anti-obesity effect of CAP is related to the changes in gut microbiota. C57BL/6 mice were fed either with high-fat diet (HFD) or HFD with CAP (HFD-CAP) for 9 weeks. We observed a significantly reduced weight gain and improved glucose tolerance in HFD-CAP-fed mice compared with HFD-fed mice. 16S rRNA gene sequencing results showed a decrease of phylum Proteobacteria in HFD-CAP-fed mice. In addition, HFD-CAP-fed mice showed a higher abundance of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on host metabolism. Further studies found that CAP directly up-regulates the expression of Mucin 2 gene Muc2 and antimicrobial protein gene Reg3g in the intestine. These data suggest that the anti-obesity effect of CAP is associated with a modest modulation of the gut microbiota.
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Background/objective: An imbalance between energy intake and expenditure leads to obesity. Increasing metabolism and thermogenesis in brown adipose tissue (BAT) can help in overcoming obesity. Here, we investigated the effect of activation of transient receptor potential vanilloid subfamily 1 (TRPV1) in the upregulation of thermogenic proteins in BAT to counter diet-induced obesity. Subjects/methods: We investigated the effect of 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. We measured the metabolic activity, respiratory quotient and BAT lipolysis. Results: 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. 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 Ca(2+) 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. CAP did not have any effect in TRPV1(-/-) mice. Conclusions: Our 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. These data suggest that TRPV1 activation is a novel strategy to counter diet-induced obesity by enhancing metabolism and energy expenditure.International Journal of Obesity accepted article preview online, 20 January 2017. doi:10.1038/ijo.2017.16.
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Chili has culinary as well as medical importance. Studies in humans, using a wide range of doses of chili intake (varying from a single meal to a continuous uptake for up to 12 weeks), concluded that it facilitates weight loss. In regard to this, the main targets of chili are fat metabolism, energy expenditure, and thermogenesis. To induce weight loss, the active substance of chili, capsaicin, activates Transient Receptor Potential Cation Channel sub-family V member 1 (TRPV1) channels) receptors causing an increase in intracellular calcium levels and triggering the sympathetic nervous system. Apart from TRPV1, chili directly reduces energy expenditure by activating Brown Adipose Tissue. Weight loss by chili is also the result of an improved control of insulin, which supports weight management and has positive effects for treatment for diseases like obesity, diabetes and cardiovascular disorders. This review summarizes the major pathways by which chili contributes to ameliorating parameters that help weight management and how the consumption of chili can help in accelerating weight loss through dietary modifications.
Background: There has been limited evidence about whether genotype-tailored advice provides extra benefits in reducing obesity-related traits compared with the benefits of conventional one-size-fits-all advice.Objective: We determined whether the disclosure of information on fat-mass and obesity-associated (FTO) genotype risk had a greater effect on a reduction of obesity-related traits in risk carriers than in nonrisk carriers across different levels of personalized nutrition.Design: A total of 683 participants (women: 51%; age range: 18–73 y) from the Food4Me randomized controlled trial were included in this analysis. Participants were randomly assigned to 4 intervention arms as follows: level 0, control group; level 1, dietary group; level 2, phenotype group; and level 3, genetic group. FTO (single nucleotide polymorphism rs9939609) was genotyped at baseline in all participants, but only subjects who were randomly assigned to level 3 were informed about their genotypes. Level 3 participants were stra
Sleeve gastrectomy, gastric bypass, gastric banding, and duodenal switch are the most common bariatric procedures performed worldwide. Ninety-five percent of bariatric operations are performed with minimally invasive laparoscopic technique. Perioperative morbidities and mortalities average around 5% and 0.2%, respectively. Long-term weight loss averages around 15% to 25% or about 80 to 100 lbs (40–50 kg). Comorbidities, including type 2 diabetes, hypertension, dyslipidemia, sleep apnea, arthritis, gastroesophageal reflux disease, and nonalcoholic fatty liver disease, improve or resolve after bariatric surgery.
Systems biology uses mathematical models to analyze large datasets and simulate system behavior. It enables integrative analysis of different types of data and can thereby provide new insight into complex biological systems. Here will be discussed the challenges of using systems medicine for advancing the development of personalized and precision medicine to treat metabolic diseases like insulin resistance, obesity, NAFLD, NASH, and cancer. It will be illustrated how the concept of genome-scale metabolic models can be used for integrative analysis of big data with the objective of identifying novel biomarkers that are foundational for personalized and precision medicine.
Objective: To review the efficacy and safety of liraglutide 3.0 mg for weight loss. Data source: A literature search was performed using PubMed and MEDLINE from 2000 to 2016. The following key terms were used alone or in combination: glucagon-like peptide-1 agonist, liraglutide, obesity, overweight, and weight loss. Additional supporting literature was identified utilizing the reference lists of the preceding articles. Study selection: Analyzed studies were published in English and investigated use of liraglutide and its impact on weight loss. Data extraction: Clinical studies with a primary focus of liraglutide use in weight loss were included in this review. Author consensus determined final study inclusion. Data synthesis: Management of obesity centers on behavior modification that includes diet and exercise; however, pharmacologic therapy may be used. Several studies have indicated that GLP-1 receptor agonists promote weight loss in patients with type 2 diabetes mellitus (T2DM). The efficacy of liraglutide 3.0 mg as a weight-loss agent in patients with and without T2DM was established in three SCALE™ clinical trials. Liraglutide 3.0 mg was generally well tolerated during clinical trials. Common adverse events were typically related to the gastrointestinal system (i.e., nausea, vomiting). Conclusion: Based on available evidence, liraglutide 3.0 mg appears to be a safe and effective addition to the pharmacologic armamentarium available for chronic weight management in the general population. However, there are limited data within the geriatric population. Clinicians should consider liraglutide's cost, route of administration, and concomitant drug therapy when deciding which patients are appropriate candidates for liraglutide therapy. Abbreviations: AE = Adverse events, AHA/ACC/TOS = American Heart Association/American College of Cardiology/ The Obesity Society, BMI = Body mass index, CV = Cardiovascular, FDA = Food and Drug Administration, GI = Gastrointestinal, GLP-1 = Glucagon-like peptide-1, HbA1c = Hemoglobin A1c, Kcal = Kilocalorie, LCD = Low-calorie diet, MTC = Medullary thyroid carcinoma, NHLBI = National Heart Lung and Blood Institute, NNH = Number needed to harm, PYE = Patient years of exposure, REMS = Risk Evaluation and Mitigation Strategy, SCALE™ = Satiety and Clinical Adiposity - Liraglutide Evidence in Non-diabetic and Diabetic individuals, T2DM = Type 2 diabetes mellitus.
Obesity is reaching global epidemic proportions as a result of factors such as high-calorie diets and lack of physical exercise. Obesity is now considered to be a medical condition, which not only contributes to the risk of developing type 2 diabetes mellitus, cardiovascular disease and cancer, but also negatively affects longevity and quality of life. To combat this epidemic, anti-obesogenic approaches are required that are safe, widely available and inexpensive. Several plants and mushrooms that are consumed in traditional Chinese medicine or as nutraceuticals contain antioxidants, fibre and other phytochemicals, and have anti-obesogenic and antidiabetic effects through the modulation of diverse cellular and physiological pathways. These effects include appetite reduction, modulation of lipid absorption and metabolism, enhancement of insulin sensitivity, thermogenesis and changes in the gut microbiota. In this Review, we describe the molecular mechanisms that underlie the anti-obesogenic and antidiabetic effects of these plants and mushrooms, and propose that combining these food items with existing anti-obesogenic approaches might help to reduce obesity and its complications.
Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.