Phytochemicals as novel agents for the induction of browning in white adipose tissue
- Yusra Azhar†1,
- Ashish Parmar†1,
- Colette N. Miller2,
- Janaiya S. Samuels1 and
- Srujana Rayalam1Email authorView ORCID ID profile
© The Author(s). 2016
Received: 25 August 2016
Accepted: 29 November 2016
Published: 3 December 2016
Obesity and its associated metabolic syndrome continue to be a health epidemic in westernized societies and is catching up in the developing world. Despite such increases, little headway has been made to reverse adverse weight gain in the global population. Few medical options exist for the treatment of obesity which points to the necessity for exploration of anti-obesity therapies including pharmaceutical and nutraceutical compounds. Defects in brown adipose tissue, a major energy dissipating organ, has been identified in the obese and is hypothesized to contribute to the overall metabolic deficit observed in obesity. Not surprisingly, considerable attention has been placed on the discovery of methods to activate brown adipose tissue. A variety of plant-derived, natural compounds have shown promise to regulate brown adipose tissue activity and enhance the lipolytic and catabolic potential of white adipose tissue. Through activation of the sympathetic nervous system, thyroid hormone signaling, and transcriptional regulation of metabolism, natural compounds such as capsaicin and resveratrol may provide a relatively safe and effective option to upregulate energy expenditure. Through utilizing the energy dissipating potential of such nutraceutical compounds, the possibility exists to provide a therapeutic solution to correct the energy imbalance that underlines obesity.
As the epidemic of obesity continues to grow, adipose tissue has increasingly become an area of focus for researchers. Adipose tissue plays an important role in the human body not just in terms of lipid accumulation but also in its endocrine functions. The expansion of white adipose tissue (WAT) and subsequent changes in circulating adipokines have been implicated in the pathogenesis of obesity . Likewise, the perturbances in the activity of brown adipose tissue (BAT), the energy dissipating organ important for thermogenesis, also play an additional role in driving the obese-state. Because of this, activation of BAT has gained attention as a therapeutic target for obesity recently . Many advancements have occurred in the area of brown fat technology, specifically relating to pathways in which BAT is functionally and physically different from WAT and various strategies that can be used to activate BAT. Discovery of brown adipocyte - like cells interspersed in WAT of human adults, termed beige or brite adipocytes , has further increased research investigating methods to activate these cells as an approach towards prevention and treatment of obesity. This review defines the current information on the function of BAT and mechanisms that drive its activation. Further, we will explore the current research on phytochemicals which have shown some promise as thermogenic agents or activators of BAT.
White and brown fat adipogenesis
The life cycle of an adipocyte begins at the stage of a multipotent stem cell, which can differentiate into multiple cell types, including myoblasts and adipocytes. Expression of various transcriptional regulators such as peroxisome proliferator-activated receptor gamma (PPARγ) drives the differentiation of adipocytes. PPARγ is a hormone receptor specific to adipocytes that has been implicated as a key enhancer of adipogenesis. Activation of PPARγ occurs early in the preadipocyte life cycle and is regulated by a variety of lipids such as triglycerides, esters, and sterols . While overexpressed C/EBPβ (CCAAT enhancer binding protein β) has the ability to promote adipogenesis in 3 T3-L1 preadipocytes, the knockout of this gene in conjunction with C/EBPδ results in a decreased number of adipocytes, leading to a reduced adipose tissue mass . The knockout of C/EBPβ gene alone showed little effect on decreasing adipose tissue mass suggesting the redundancy of function by C/EBP family transcription factors. Nevertheless, early expression of C/EBPβ is required for adipogenesis and activates C/EBPα and PPARγ, the key transcription factors that work together to in turn activate a group of genes that promote adipogenesis (reviewed in ). The expression of these two genes leads them to positively cross activate one another and perpetuate the adipocyte lineage. Interestingly, PPARγ is not only involved in white adipogenesis but also plays a key role in the induction of brown adipocyte-specific genes (reviewed in ).
Unlike the majority of white adipocytes, the adipocytes found in BAT are derived from the Myf5 lineage and thus share a common precursor with skeletal muscle . PR domain containing 16 (PRDM16) is a determining transcription factor for BAT development and overexpression of this protein results in browning of primary visceral preadipocytes . PRDM16 promotes the induction of BAT genes by partnering with peroxisome proliferator-activated receptor γ coactivator (PGC-1) α and β. PGC-1α is a coactivator of PPARγ and it primarily controls mitochondrial biogenesis through the induction of uncoupling proteins such as uncoupling protein 1 (UCP1) . Sirtuin-1 (SIRT1) is another important regulator of thermogenesis and its primary role is to deacetylate PPARγ . Deacetylation of PPARγ is required to recruit PRDM16 which further leads to the induction of BAT genes and repression of WAT genes . Association between these important transcription factors leads to the development and regulation of BAT function.
Thermogenesis is the process of converting chemical energy into heat. While shivering thermogenesis makes use of rapid muscular twitches to produce heat, BAT is specialized to generate heat in a process called non-shivering or adaptive thermogenesis . BAT plays a pivotal role in protecting animals from hypothermia and is used during the periods of hibernation. It has long been known that BAT is present in newborns, but a number of recent studies conducted through the combined utilization of 18-FDG PET and CT show that human adults do have brown fat [14, 15] paving way to a new area in research relating to metabolic and obesity therapies . The functional properties of BAT that makes it different from WAT mainly come from the lack of a large, unilocular lipid droplet and the presence of numerous mitochondria which allows for the production of energy. Mitochondria in brown adipocytes have low levels of ATP synthase and so cannot utilize the proton gradient of mitochondria to produce ATP. Instead, they employ UCP1 which uncouples cellular respiration and ATP synthesis, and thus results in the production of heat . In vivo studies have shown that mice that lack the Ucp1 gene preferentially express an obese phenotype . These studies show the importance of BAT thermogenesis and its role in preventing obesity.
The sympathetic nervous system plays a significant role in the regulation of BAT thermogenesis. The release of catecholamines such as norepinephrine as a result of sympathetic stimulation from cold induction through the transient receptor potential (TRP) cation channels (members A1, M8, and V1) leads to the activation of the mitochondria in BAT which further leads to heat generation. The subsequent binding of norepinephrine to β-3 adrenergic receptors causes the secretion of free fatty acids from BAT which is the main energy source for UCP1 driven thermogenesis .
Thyroid hormone is an additional critical driver of the thermogenic response and brown adipose tissue activation. The conventional signaling cascade for thyroid hormone starts from the release of thyroxin (T4) from thyroid gland upon stimulation by the pituitary. Once released, T4 travels through the bloodstream to target tissues that express the necessary deiodinase (specifically DIO2) for the creation of triiodothyronine T3 . Relative to other tissues, brown fat expresses a relatively large amount of deiodinase  and thus is reactive to changes in circulating T4 concentrations, in addition to the sympathetic activation that upregulates deiodinase expression . The UCP1 promoter contains a transcriptional regulatory region for the thyroid hormone receptor β . Thus, thyroid hormone can directly upregulate the expression of UCP1 and serves as a necessary regulator for both brown adipogenesis and thermogenesis. Further, the α-subtype of the thyroid hormone receptor also regulates the expression of the β-adrenergic receptors , thereby sensitizing brown fat to sympathetic activation. Secondarily, active T3 can be released from tissues and interact with additional cell types not believed previously to be regulated by thyroid hormone. Of most interest, T3 has demonstrated the ability to activate the ventral medial hypothalamus which serves as a central mediator of the sympathetic nervous system . Through this mechanism, T3 appears to further regulate sympathetic activity and drive the activation of BAT in addition to direct transcriptional control of UCP1. It should be noted that the levels of T3 in BAT is influenced by DIO2 activity, which in turn is inhibited by T4 and activated by adrenergic stimulation. Thyroid hormone and the sympathetic nervous system are thus intimately tied, both co-regulating their respective responses and together drive the body’s response to cold .
Phytochemicals in obesity
Natural, plant-derived compounds have made up the backbone of many of the synthetic drugs which are used today. The use of natural products for medical purposes dates back thousands of years; however their use in the discovery and development of modern drugs has only occurred since the early 19th century. Nearly 50% of drug approvals in the last 30 years came from compounds that were directly or indirectly derived from natural products . The safety of these synthetic compounds however is hotly debated. Recent drug recalls and fatalities have led to resurgence in research on natural products because of their ease of use and efficacy. In particular, certain anti-obesity medications are removed from market owing to their adverse side effects . In this context, natural products have been studied for their role in the regulation of adipocyte life cycle . Phytochemicals can target different stages in the adipocyte life cycle by decreasing adipogenesis, inducing lipolysis, inducing adipocyte-apoptosis and by inducing transdifferentiation of white to brown-like adipocytes . While the terms nutraceuticals, phytochemicals and bioactives are often used synonymously, it should be noted that phytochemicals are non-nutrient bioactive compounds found in fruits, vegetables and other parts of plants. Nutraceuticals on the other hand are broadly defined as food supplements that are used to improve health. This review focuses primarily on the effects of purified bioactive compounds rather than the plant extracts. In the coming sections, we discuss some of the phytochemicals that have shown promise as activators of BAT or have potential to act as thermogenic agents for future applications in the prevention and treatment of obesity and metabolic syndrome.
Resveratrol is a polyphenol found in a number of plants including the skin of grapes and several other types of berries. Numerous studies have indicated the anti-oxidant properties of this compound and the research around resveratrol continues to grow into other therapeutic uses such as cancer suppression and improving insulin sensitivity . Studies on resveratrol’s effects on inflammation and thermogenesis have shown a decrease in the production of inducible nitric oxide synthase 2 (iNOS-2) and an increase in the markers of mitochondrial biogenesis contributing to an overall increase in energy expenditure .
In regards to obesity and adipogenesis, resveratrol decreases adipocyte differentiation and lipid accumulation via a decrease in the expression of key transcription factors involved in adipogenesis like PPARγ and C/EBPα . Furthermore, SIRT1 in WAT is activated by resveratrol to promote the mobilization of fat from adipocytes [31, 33]. Unsurprisingly, resveratrol has shown the possibility to also regulate BAT activity. Alberdi et al. found elevated levels of UCP1 expression in the BAT and skeletal muscle of mice that were fed a diet supplemented with resveratrol . Further, oral administration of resveratrol in mice also showed an increase in SIRT1 expression in WAT . Authors proposed that the increased UCP1 expression seen in mice is due to stimulation of SIRT1 contributing to the improved energy efficiency and decreased fat mass. On the other hand, Um et al. reported that resveratrol fails to upregulate thermogenic proteins like PGC1α in adenosine monophosphate activated kinase (AMPK) null mice and AMPK null mice are resistant to the thermogenic effects induced by resveratrol . Subsequent studies however revealed that SIRT1 plays a key role in potentiating resveratrol-induced activation of AMPK and improving mitochondrial function . These findings suggest that resveratrol – induced increase in whole-body energy expenditure might be partly mediated by the induction of browning in WAT.
Curcumin is a flavonoid found in turmeric, a spice popular in south Asian cuisine. Administration of curcumin has been shown to improve insulin sensitivity and increase weight loss in insulin-resistant obese mice .
Curcumin inhibits the early stages of adipogenesis in 3 T3-L1 adipocytes by lowering the expression of PPARγ and C/EBPα leading to a decrease in lipid accumulation . Furthermore, curcumin-treated mice have lowered amount of free fatty acids, triglycerides, and improvement of insulin resistance and hyperglycemia suggesting its anti-diabetic potential . Subsequently, curcumin has been shown to induce browning of 3 T3-L1 cells as indicated through increased expression of brown fat markers including PGC-1α, PPARγ, and UCP1 in dose dependent manner . Further, T-box transcription factor 1 (TBX1), a beige specific marker, was significantly increased in 3 T3-L1 and primary white adipocytes following treatment with curcumin. Such findings have also been replicated in the mouse model where curcumin administration (50 or 100 mg/kg) resulted in the increased appearance of beige adipocytes in subcutaneous and inguinal WAT. Within this study, curcumin treatment resulted in the increased expression of many beige specific markers such as Ucp1, Pgc1α, Dio2 and Prdm16. Cold tolerance tests conducted on mice showed that curcumin treated mice had increased body temperature compared to temperatures around 4 °C .
Additionally curcumin treatment stimulated the emergence of beige cells in inguinal and subcutaneous WAT but not epididymal WAT. The authors further postulated that the curcumin-induced browning of WAT is mediated by the upregulation of β3-adrenergic receptor expression and elevation of plasma levels of norepinephrine by curcumin . Not surprisingly, curcumin appears to act through the transient receptor potential vanilloid receptor 1 (TRPV1) receptors located in the intestinal jejunum and thus may have downstream effects on both WAT and BAT through direct modulation of the sympathetic nervous system .
Soy isoflavones are phytoestrogens which have shown promise in lipid metabolism. A recent human clinical trial with isoflavone supplemented soy probiotic for 42 days, showed an improvement in the lipid profile of moderately hypercholesteremic men . One major photochemical belonging to this group of soy isoflavones is genistein. Genistein is found primarily in soybeans and broad beans, which are harvested in parts of Western Asia and Europe. Effects of genistein on cancer prevention have been under investigation for a long time and these effects are attributed to the epigenetic effects of genistein. Genistein was shown to target all the epigenetic mechanisms like altering DNA methylation, and histone modifications that control the accessibility of genes of interest (reviewed in ).
Not only has genistein been described as a PPARγ agonist , but recent studies provide evidence that genistein has the potential to promote characteristics of beiging in WAT. High dose treatment of genistein (50–100 μM) on NIH3T3-L1 cells was shown to result in the increased expression of SIRT1 and its downstream partner, UCP1 . Such an effect was also observed in primary culture whereas genistein increased mitochondrial biogenesis by upregulating PGC-1α . Recent research however has shown confounding evidence on genistein’s anti-obesity effects. In 3 T3-L1 and human primary adipocytes, genistein has shown to inhibit adipogenesis at concentrations of 50 μM . However, Zanella et al. found that using minimal doses (plasma concentration of 4 μM) in mice models, genistein promoted 3 T3-L1 adipogenesis rather than inhibiting it . This evidence highlights the importance of dose range in the effect of phytochemicals on the cellular mechanisms of adipocyte differentiation. Genistein and its fellow isoflavone resveratrol have shown their ability to defend against metabolic syndrome by regulating lipid and glucose metabolism. Lastly, it is important to mention that the use of both resveratrol and genistein has shown to have a greater effect on adipogenesis and apoptosis of adipocytes rather than each of these compounds alone . Thus, it is likely that the combination treatments of both genistein and resveratrol may lead to an even greater anti-obesity effect and activation of BAT which has not yet been explored.
Guggulsterone (GS) is the bioactive gum resin derived from the bark of the Commiphora mukul tree predominantly found in India, Bangladesh and Pakistan. Cholesterol lowering effects of GS were first reported in hyperlipidemic rabbits  and since then, numerous animal and clinical studies have been conducted to demonstrate the effects of GS on lipid, cholesterol, and triglyceride levels . However, there is a lack of reliability in several of the human studies that have attempted to explore and better understand the potential of GS due to flawed techniques . In contrast, in vitro studies investigating the effects of GS on adiposity have found more success and clearly demonstrate i) inhibition of adipogenesis , ii) increase glucose uptake in insulin resistant conditions , iii) lipolytic effects in combination with other agents such as genistein  xanthohumol , and hormonal metabolite of vitamin D . To date there is no scientific-based research that investigated the ability of GS to stimulate mitochondrial uncoupling and thus increase metabolic rate.
Hop plants or Humulus lupulus are more widely known for their usage in the beer brewing process but far less known are the historic uses of hops in traditional medicine. Xanthohumol, derived as the prenylated flavonoid of female inflorescences of the hop plant, has some promising anti-obesity effects. In addition to its in vitro effects on inhibiting adipogenesis  and causing apoptosis in mature adipocytes , xanthohumol also extends to in vivo effects where it is found to protect against diet induced obesity . Xanthohumol increases energy expenditure which has been demonstrated in various cell types including white and brown preadipocytes, hepatocytes and myocytes . Administration of xanthohumol increases oxygen consumption levels while ATP synthase was inhibited indicating the uncoupling of mitochondria.
The mechanism of xanthohumol’s effects on cellular metabolism is through increasing the production of reactive oxidative species, which leads to the activation of 5’ adenosine monophosphate-activated protein kinase AMPK and PGC1-α . Interestingly, xanthohumol, like several other phytochemicals, exhibits hormesis effect, wherein low dose of xanthohumol increased uncoupling and oxygen consumption while high dose inhibited respiration in an ROS-dependent manner. Nevertheless, xanthohumol may ameliorate metabolic syndrome, at least in part, through mitochondrial uncoupling and stress response induction . Xanthohumol also has an effect on bile acid generation which may lead to activation of bile acid G-protein coupled receptor TGR5 and downstream activation of T3 and ultimately UCP1 (Fig. 2). The uncoupling ability of xanthohumol can be attributed to its nonpolar nature and the ease of ability to which it can cross the plasma membrane and potentially activate transcription nuclear receptors which regulate metabolic genes .
While xanthohumol has demonstrated anti-obesity potential in rodent studies where dietary xanthohumol-rich hop extract significantly lowered body weight gain, its effects have been more related to WAT and very little attention has been placed on BAT . Administering mature hop plants to mice was found to induce thermogenesis in brown adipocytes, which is demonstrated by increased expression of PPARγ and UCP1 . Because xanthohumol has shown the potential to upregulate oxygen consumption rates and chemical uncoupling, it can be suggested that xanthohumol may be inducing such metabolic changes through systemic thyroid hormone signaling. Small, but significant increases in T4 binding globulin was seen following xanthohumol administration  and additionally, xanthohumol also upregulated iodide uptake by thyrocytes indicating a likely direct role in promoting thyroid hormone biosynthesis . Future research should be placed on the metabolic impacts of xanthohumol and thyroid hormone signaling and further research is needed to definitively demonstrate xanthohumol’s potential on BAT activity
Naringenin, a flavonoid found in citrus fruits such as grapefruits and oranges, has also been recognized as a bioactive compound with protective properties against adiposity. Significant evidence shows that naringenin prevents metabolic syndrome by inhibiting diet-induced dyslipidemia , lipogenesis  and adipogenesis .
Inflammation of the adipose tissue is one of the hallmarks of obesity. This inflammation is derived from an infiltration of macrophages in the adipose tissue . The protective effects of naringenin were elucidated in one study where mice fed a high fat diet along with naringenin had decreased levels of macrophage infiltration and thus lower obesity-related adipose tissue inflammation . Another study shows naringenin administered to rats in conjunction with cholesterol-rich diet reduced total cholesterol and triglyceride levels as well as increased antioxidant activity .
Furthermore, naringenin-fed mice also show an upregulation in gene expression of PPARα, a regulator of lipid catabolism . In brown fat activators, PPARα is linked to fatty acid oxidation as a direct result of UCP1 induction and thermogenesis . Further, PPARα-dependent induction of UCP1 is also found in WAT and is suggestive of the beiging potential of naringenin . Preliminary studies conducted in our lab showed that naringenin at 25 and 50 μM concentration induced a dose-dependent increase in the expression of UCP1 and SIRT1 in primary human omental adipocytes. These preliminary experiments suggest a possible potential for naringenin as a thermogenic agent with therapeutic applications in obesity and metabolic syndrome.
Another flavonoid found to have beneficial anti-obesity effects is quercetin (3,3′,4′,5,7-pentahydroxyflavone). Commonly found in high concentrations in apples, broccoli, berries, onions, leafy vegetables and asparagus, quercetin is a polyphenol that has significant data showing its beneficial effects on cardiovascular system and lipid homeostasis . Quercetin supplementation in high fat diet-induced obese mice protects against diet-induced obesity by increasing energy expenditure and inflammation . Other studies demonstrating the protective effects of quercetin supplementation in mice fed high fat diet found lower body weight gain, triglycerides, and plasma cholesterol levels as a result of improved regulation of metabolic genes . Quercetin also improved metabolic conditions in obese mice, as demonstrated by improved dyslipidemic state . In vitro studies of quercetin rich extract showed inhibition of adipogenesis, decreased lipid accumulation and apoptosis of mature white adipocytes .
Dietary quercetin has also shown the ability to increase the expression of UCP1 and thus thermogenesis in mice fed with quercetin-enriched diet . In this study, quercetin was shown to inhibit polarization of bone marrow-derived macrophages towards pro-inflammatory M1 lineage through an AMPK/SIRT1-mediated mechanism. Given the well-established role of SIRT1 and AMPK in energy expenditure  it is likely that quercetin has the potential in induce browning of WAT. Although in vitro and in vivo studies provide significant data in support of quercetin related response to adiposity and obesity, the direct effects of quercetin on white adipocyte transdifferentiation needs to be further researched.
Capsaicinoids are a group of phytochemicals including, but not limited to, capsaicins and capsinoids. The capsaicinoid family consists of capsaicin, dihydrocapsaicin, nordihydrocapsaicin and others. There has been extensive research showing that capsaicin has anti-obesity, anti-diabetic, and anti-inflammatory characteristics. Recent studies also indicate that capsaicin acts by activating the sympathetic system to induce BAT thermogenesis and reduce fat accumulation .
Administration of capsaicin in mice has shown to induce thermogenesis via the activation of BAT . This is evidenced by the increase in markers related to mitochondrial biogenesis such as PPARγ, PGC-1α and UCP1 . Capsaicin also induces the development of beige adipocytes at an early stage of adipogenesis . The effect of capsaicin/capsinoid treatment has been compared to that of chronic cold exposure, in which sympathetic stimulation results in the activation of BAT . Similarly to the aforementioned curcumin, capsaicin binds to the intestinal transient receptor potential vanilloid 1(TRPV1) receptor, also referred to as the capsaicin receptor, thereby launching the sympathetic response observed with treatment . Surprisingly, capsaicin has also been proven to be harmful to humans and these harmful effects are mediated, in part, by the capsaicin receptor, TRPV1 [90–92].
Capsinoids are capsaicin analogs, similar in function to capsaicins, but are far less pungent thus, less toxic, and physiologically compromising to humans. The low pungency characteristic of the naturally occurring ‘CH-19 Sweet’ pepper makes them edible in comparison to capsaicinoids and therefore, are an attractive target for anti-obesity therapy.
It has been demonstrated that capsinoids decrease fat accumulation in adipocytes both in vitro and in vivo in mice . Acute administration of capsinoids augments energy expenditure, sympathetic nervous system activation, and thermogenesis with comparable efficacy to capsaicins. Capsinoids are TRPV1 agonists and increased energy expenditure and fat oxidation is dependent on TRPV1, much like capsaicin, but the capsinoid sensory receptor is found in the gastrointestinal tract while capsaicin’s sensory receptor is located on the tongue. The difference in the location of sensory neurons and capsinoid’s subtle pungency decreases its likelihood for hyperalgesia effects in comparison to capsaicin .
As an inducer of the browning of WAT, a diet supplemented with capsinoids fed to mice kept at 17 °C for 8 weeks, significantly increased energy expenditure, but not at 25 °C. This was confirmed by increased BAT and beige specific gene markers such as Ucp1, Pgc1α, Cidea, Cd137, and Tmem26, in inguinal WAT, respectively. It has been shown that capsinoids upregulated the expression of the PRDM16 protein in inguinal WAT under ambient and mildly cold temperatures upon β-adrenergic stimulation . Yoneshiro et al. demonstrated that acute administration of capsinoids increased energy expenditure in BAT-positive subjects, but not in subjects without metabolically active BAT, under cold exposure . Capsinoids seem to be promising in that they are accompanied with fewer side effects than capsaicins but there are conflicting studies of their potential as browning agents. Therefore, further research needs to establish its role in the browning of WAT and the associated underlying molecular mechanisms.
Cinnamaldehyde is a pungent spice extracted from the plant cassia and is the most abundant phytochemical in cinnamon . Used since the medieval times for medicinal purposes, cinnamaldehyde has now been identified to have multiple therapeutic uses such as anti-diabetic, anti-arthritic, anti-inflammatory, anti-microbial, and anti-cancer effects . Cinnamaldehyde activates TRP cation channels, similar to capsaicinoids. More specifically, cinnamaldehyde activates the cold-gated ion channel, transient receptor potential Ankyrin subtype 1, TRPA1 . It has been shown that the cinnamaldehyde acts as an agonist to TRPA1 and upregulates adrenaline secretion in rats . This adrenaline secretion stimulation by cinnamaldehyde could explain the induction of thermogenesis and inhibition of heat diffusion in mice .
Cinnamon decreased lipid accumulation in vitro in 3T3-L1 preadipocytes and the expression of adipogenic transcription factors PPARγ, C/EBPα and SREBP-1c during adipocyte differentiation . In a dose-dependent manner, cinnamaldehyde also decreased visceral fat deposition, partly mediated by the activation of interscapular BAT, as evidenced by the upregulation of UCP1 expression levels, in high fat and high sucrose diet-fed mice . Taken together, this data suggests the potential of cinnamaldehyde to act as a browning agent and exert its anti-obesity effects with future research.
Fucoxanthin, extracted from edible brown alga, is a carotenoid known to have anti-carcinogenic, anti-inflammatory, anti-diabetic and apoptotic effects in metastatic cells. Fucoxanthin has been shown to ameliorate the progression of obesity in vitro and in vivo in mice and human models . Fucoxanthin reduced lipid accumulation accompanied by a decrease in PPARγ expression in 3T3-L1 adipocytes . Kang et al. demonstrated that fucoxanthin stimulated 3T3-L1 adipogenesis at an early stage mediated by an increase in the expression of PPARγ and C/EBPα and the adipocyte differentiation marker, aP2. However, fucoxanthin significantly downregulated the adipogenesis of 3T3-L1 adipocytes at the intermediate and late stages of differentiation, and the expression of PPARγ, C/EBPα and SREBP1c transcription factors .
Maeda et al. investigated the potential anti-obesity and anti-diabetic effects of fucoxanthin supplemented diets in rodent models. Results from these studies suggested that fucoxanthin significantly lowered WAT weight gain in mice with high fat diet-induced obesity, as well as mRNA levels of leptin in WAT. Further, fucoxanthin stabilized blood glucose and insulin levels and downregulated monocyte chemoattractant protein-1, MCP-1, expression in WAT of diet-induced obese mice. MCP-1, a protein secreted from adipose tissues, stimulates macrophage accumulation and the production of pro-inflammatory mediators. Finally, β3-adrenergic receptor, Adrb3, mRNA expression levels were upregulated in WAT of mice maintained on fucoxanthin high fat diets. As discussed earlier, Adrb3, expressed in both BAT and WAT, is suggested to play a role in lipolysis and thermogenesis .
Fucoxanthin-fed obese mice experienced a decrease in WAT weight as well as a significant upregulation in the expression of UCP1 protein and mRNA in WAT, resulting in energy expenditure in the form of heat and fatty acid oxidation in WAT . This increase in UCP1 expression was nearly diminished in WAT in mice maintained on a control diet. In another study of Maeda and his colleagues, fucoxanthin significantly decreased the body weight of mice on high fat diets . Overall, these studies suggest that fucoxanthin may have promising anti-diabetic and anti-obesity effects and deserve more research focus, primarily in human subjects.
Adenosine monophosphate-activated protein kinase
Brown adipose tissue
CCAAT enhancer binding protein
Type 2 deiodinase
Inducible nitric oxide synthase
Peroxisome proliferator-activated receptor γ coactivator
Peroxisome proliferator-activated receptor
PR domain containing 16
Sterol regulatory element-binding protein 1c
T-box transcription factor 1
Takeda G-protein coupled receptor 5
Transient receptor potential
Uncoupling protein 1
White adipose tissue
The authors would like to thank Philadelphia College of Osteopathic Medicine – GA campus for the research facilities and support through the CSO and CCDA funds.
YA and AP performed literature research, wrote and reviewed the manuscript; YA and AP contributed equally to the manuscript. JSS wrote, edited and reviewed the manuscript. CNM and SR reviewed and edited the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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- Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184–223.PubMedPubMed CentralView ArticleGoogle Scholar
- Poher AL, Altirriba J, Veyrat-Durebex C, Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Front Physiol. 2015;6:4.PubMedPubMed CentralView ArticleGoogle Scholar
- Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252–63.PubMedView ArticleGoogle Scholar
- Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999;4(4):611–7.PubMedView ArticleGoogle Scholar
- Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997;16(24):7432–43.PubMedPubMed CentralView ArticleGoogle Scholar
- Tang QQ, Lane MD. Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem. 2012;81(1):715–36.PubMedView ArticleGoogle Scholar
- Lo KA, Sun L. Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep. 2013;33(5):e00065.PubMedPubMed CentralView ArticleGoogle Scholar
- Seale P, Kajimura S, Spiegelman BM. Transcriptional control of brown adipocyte development and physiological function—of mice and men. Genes Dev. 2009;23(7):788–97.PubMedPubMed CentralView ArticleGoogle Scholar
- Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of pparγ. Cell. 2012;150(3):620–32.PubMedPubMed CentralView ArticleGoogle Scholar
- Kleiner S, Mepani RJ, Laznik D, Ye L, Jurczak MJ, Jornayvaz FR, Estall JL, Chatterjee Bhowmick D, Shulman GI, Spiegelman BM. Development of insulin resistance in mice lacking PGC-1α in adipose tissues. Proc Natl Acad Sci U S A. 2012;109(24):9635–40.PubMedPubMed CentralView ArticleGoogle Scholar
- Nedergaard J, Petrovic N, Lindgren EM, Jacobsson A, Cannon B. PPARγ in the control of brown adipocyte differentiation. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2005;1740(2):293–304.View ArticleGoogle Scholar
- Jimenez-Preitner M, Berney X, Uldry M, Vitali A, Cinti S, Ledford JG, Thorens B. Plac8 is an inducer of C/EBPbeta required for brown fat differentiation, thermoregulation, and control of body weight. Cell Metab. 2011;14(5):658–70.PubMedView ArticleGoogle Scholar
- Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277–359.PubMedView ArticleGoogle Scholar
- Gifford A, Towse TF, Walker RC, Avison MJ, Welch EB. Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging. Am J Physiol Endocrinol Metab. 2016;311(1):E95–104.PubMedView ArticleGoogle Scholar
- 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):1783–90.PubMedPubMed CentralView ArticleGoogle Scholar
- Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360(15):1509–17.PubMedPubMed CentralView ArticleGoogle Scholar
- Kajimura S, Saito M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol. 2014;76:225–49.PubMedView ArticleGoogle Scholar
- Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9(2):203–9.PubMedView ArticleGoogle Scholar
- Saito M. Brown adipose tissue as a regulator of energy expenditure and body fat in humans. Diabetes Metab J. 2013;37(1):22–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006;116(10):2571–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Bates JM, St Germain DL, Galton VA. Expression profiles of the three iodothyronine deiodinases, D1, D2, and D3, in the developing rat. Endocrinology. 1999;140(2):844–51.PubMedGoogle Scholar
- Silva JE, Larsen PR. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature. 1983;305(5936):712–3.PubMedView ArticleGoogle Scholar
- Bianco AC, Silva JE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest. 1987;79(1):295–300.PubMedPubMed CentralView ArticleGoogle Scholar
- Solmonson A, Mills EM. Uncoupling proteins and the molecular mechanisms of thyroid thermogenesis. Endocrinology. 2016;157(2):455–62.PubMedView ArticleGoogle Scholar
- Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16(9):1001–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Rubio A, Raasmaja A, Silva JE. Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. Endocrinology. 1995;136(8):3277–84.PubMedGoogle Scholar
- Veeresham C. Natural products derived from plants as a source of drugs. J Adv Pharm Technol Res. 2012;3(4):200–1.PubMedPubMed CentralView ArticleGoogle Scholar
- Chaput JP, St-Pierre S, Tremblay A. Currently available drugs for the treatment of obesity: Sibutramine and orlistat. Mini Rev Med Chem. 2007;7(1):3–10.PubMedView ArticleGoogle Scholar
- Rayalam S, Della-Fera MA, Baile CA. Phytochemicals and regulation of the adipocyte life cycle. J Nutr Biochem. 2008;19(11):717–26.PubMedView ArticleGoogle Scholar
- Colitti M, Grasso S. Nutraceuticals and regulation of adipocyte life: premises or promises. BioFactors. 2014;40(4):398–418.PubMedView ArticleGoogle Scholar
- Leiherer A, Mundlein A, Drexel H. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vasc Pharmacol. 2013;58(1–2):3–20.View ArticleGoogle Scholar
- Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem. 2013;141(2):1530–5.PubMedView ArticleGoogle Scholar
- Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3 T3-L1 adipocytes. Phytother Res. 2008;22(10):1367–71.PubMedView ArticleGoogle Scholar
- Andrade JMO, Frade ACM, Guimarães JB, Freitas KM, Lopes MTP, Guimarães ALS, de Paula AMB, Coimbra CC, Santos SHS. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur J Nutr. 2014;53(7):1503–10.PubMedView ArticleGoogle Scholar
- Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59(3):554–63.PubMedView ArticleGoogle Scholar
- Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15(5):675–90.PubMedPubMed CentralView ArticleGoogle Scholar
- Seo KI, Choi MS, Jung UJ, Kim HJ, Yeo J, Jeon SM, Lee MK. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. Mol Nutr Food Res. 2008;52(9):995–1004.PubMedView ArticleGoogle Scholar
- Ejaz A, Wu D, Kwan P, Meydani M. Curcumin inhibits adipogenesis in 3 T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. J Nutr. 2009;139(5):919–25.PubMedView ArticleGoogle Scholar
- Lone J, Choi JH, Kim SW, Yun JW. Curcumin induces brown fat-like phenotype in 3 T3-L1 and primary white adipocytes. J Nutr Biochem. 2016;27:193–202.PubMedView ArticleGoogle Scholar
- Wang S, Wang X, Ye Z, Xu C, Zhang M, Ruan B, Wei M, Jiang Y, Zhang Y, Wang L, et al. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochem Biophys Res Commun. 2015;466(2):247–53.PubMedView ArticleGoogle Scholar
- Zhi L, Dong L, Kong D, Sun B, Sun Q, Grundy D, Zhang G, Rong W. Curcumin acts via transient receptor potential vanilloid-1 receptors to inhibit gut nociception and reverses visceral hyperalgesia. Neurogastroenterol Motil. 2013;25(6):e429–40.PubMedView ArticleGoogle Scholar
- Cavallini DC, Manzoni MS, Bedani R, Roselino MN, Celiberto LS, Vendramini RC, de Valdez G, Abdalla DS, Pinto RA, Rosetto D, et al. Probiotic Soy product supplemented with isoflavones improves the lipid profile of moderately hypercholesterolemic Men: a randomized controlled trial. Nutrients. 2016;8(1):52.View ArticleGoogle Scholar
- Pudenz M, Roth K, Gerhauser C. Impact of soy isoflavones on the epigenome in cancer prevention. Nutrients. 2014;6(10):4218–72.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, et al. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARgamma): a review. Biochem Pharmacol. 2014;92(1):73–89.PubMedPubMed CentralView ArticleGoogle Scholar
- Aziz S, Wakeling L, Miwa S, Hesketh J, Ford D. Genistein promotes a gene expression profile characteristic of brown or beige, rather than white, adipocytes and increases Sirt1 expression in mouse NIH3T3-L1 cells. In: Proceedings of The Physiological Society. The Physiological Society; 2014.
- Rasbach KA, Schnellmann RG. Isoflavones promote mitochondrial biogenesis. J Pharmacol Exp Ther. 2008;325(2):536–43.PubMedView ArticleGoogle Scholar
- Zhang M, Ikeda K, Xu J-W, Yamori Y, Gao X-M, Zhang B-L. Genistein suppresses adipogenesis of 3 T3-L1 cells via multiple signal pathways. Phytother Res. 2009;23(5):713–8.PubMedView ArticleGoogle Scholar
- Zanella I, Marrazzo E, Biasiotto G, Penza M, Romani A, Vignolini P, Caimi L, Di Lorenzo D. Soy and the soy isoflavone genistein promote adipose tissue development in male mice on a low-fat diet. Eur J Nutr. 2015;54(7):1095–107.PubMedView ArticleGoogle Scholar
- Park HJ, Yang JY, Ambati S, Della-Fera MA, Hausman DB, Rayalam S, Baile CA. Combined effects of genistein, quercetin, and resveratrol in human and 3 T3-L1 adipocytes. J Med Food. 2008;11(4):773–83.PubMedView ArticleGoogle Scholar
- Satyavati GV, Dwarakanath C, Tripathi SN. Experimental studies on the hypocholesterolemic effect of Commiphora mukul. Engl. (Guggul). Indian J Med Res. 1969;57(10):1950–62.PubMedGoogle Scholar
- Urizar NL, Moore DD. GUGULIPID: a natural cholesterol-lowering agent. Annu Rev Nutr. 2003;23:303–13.PubMedView ArticleGoogle Scholar
- Ulbricht C, Basch E, Szapary P, Hammerness P, Axentsev S, Boon H, Kroll D, Garraway L, Vora M, Woods J. Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration. Complement Ther Med. 2005;13(4):279–90.PubMedView ArticleGoogle Scholar
- Yang JY, Della-Fera MA, Baile CA. Guggulsterone inhibits adipocyte differentiation and induces apoptosis in 3 T3-L1 cells. Obesity (Silver Spring). 2008;16(1):16–22.View ArticleGoogle Scholar
- Sharma B, Salunke R, Srivastava S, Majumder C, Roy P. Effects of guggulsterone isolated from Commiphora mukul in high fat diet induced diabetic rats. Food Chem Toxicol. 2009;47(10):2631–9.PubMedView ArticleGoogle Scholar
- Yang JY, Della-Fera MA, Rayalam S, Ambati S, Baile CA. Enhanced pro-apoptotic and anti-adipogenic effects of genistein plus guggulsterone in 3 T3-L1 adipocytes. BioFactors. 2007;30(3):159–69.PubMedView ArticleGoogle Scholar
- Rayalam S, Yang JY, Della-Fera MA, Park HJ, Ambati S, Baile CA. Anti-obesity effects of xanthohumol plus guggulsterone in 3 T3-L1 adipocytes. J Med Food. 2009;12(4):846–53.PubMedView ArticleGoogle Scholar
- Rayalam S, Della-Fera MA, Ambati S, Boyan B, Baile CA. Enhanced effects of guggulsterone plus 1,25(OH)2D3 on 3 T3-L1 adipocytes. Biochem Biophys Res Commun. 2007;364(3):450–6.PubMedView ArticleGoogle Scholar
- Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ, Moore DD. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science. 2002;296(5573):1703–6.PubMedView ArticleGoogle Scholar
- Tripathi YB, Malhotra OP, Tripathi SN. Thyroid Stimulating Action of Z-Guggulsterone Obtained from Commiphora mukul. Planta Med. 1984;50(1):78–80.View ArticleGoogle Scholar
- Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9.PubMedView ArticleGoogle Scholar
- Stepanov V, Stankov K, Mikov M. The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. J Recept Signal Transduct Res. 2013;33(4):213–23.PubMedView ArticleGoogle Scholar
- Martinez de Mena R, Scanlan TS, Obregon MJ. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology. 2010;151(10):5074–83.PubMedView ArticleGoogle Scholar
- Rayalam S, Yang JY, Della-Fera MA, Baile CA. Novel molecular targets for prevention of obesity and osteoporosis. J Nutr Biochem. 2011;22(12):1099–104.PubMedView ArticleGoogle Scholar
- Kiyofuji A, Yui K, Takahashi K, Osada K. Effects of xanthohumol-rich hop extract on the differentiation of preadipocytes. J Oleo Sci. 2014;63(6):593–7.PubMedView ArticleGoogle Scholar
- Yang JY, Della-Fera MA, Rayalam S, Baile CA. Effect of xanthohumol and isoxanthohumol on 3 T3-L1 cell apoptosis and adipogenesis. Apoptosis. 2007;12(11):1953–63.PubMedView ArticleGoogle Scholar
- Yui K, Kiyofuji A, Osada K. Effects of xanthohumol-rich extract from the hop on fatty acid metabolism in rats fed a high-fat diet. J Oleo Sci. 2014;63(2):159–68.PubMedView ArticleGoogle Scholar
- Kirkwood JS, Legette LL, Miranda CL, Jiang Y, Stevens JF. A metabolomics-driven elucidation of the anti-obesity mechanisms of xanthohumol. J Biol Chem. 2013;288(26):19000–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Morimoto-Kobayashi Y, Ohara K, Takahashi C, Kitao S, Wang G, Taniguchi Y, Katayama M, Nagai K. Matured Hop bittering components induce thermogenesis in brown adipose tissue via sympathetic nerve activity. PLoS One. 2015;10(6), e0131042.PubMedPubMed CentralView ArticleGoogle Scholar
- Radovic B, Hussong R, Gerhauser C, Meinl W, Frank N, Becker H, Kohrle J. Xanthohumol, a prenylated chalcone from hops, modulates hepatic expression of genes involved in thyroid hormone distribution and metabolism. Mol Nutr Food Res. 2010;54 Suppl 2:S225–35.PubMedView ArticleGoogle Scholar
- Radovic B, Schmutzler C, Kohrle J. Xanthohumol stimulates iodide uptake in rat thyroid-derived FRTL-5 cells. Mol Nutr Food Res. 2005;49(9):832–6.PubMedView ArticleGoogle Scholar
- Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Markle JM, Hegele RA, Huff MW. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes. 2009;58(10):2198–210.PubMedPubMed CentralView ArticleGoogle Scholar
- Assini JM, Mulvihill EE, Sutherland BG, Telford DE, Sawyez CG, Felder SL, Chhoker S, Edwards JY, Gros R, Huff MW. Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr(-)/(-) mice. J Lipid Res. 2013;54(3):711–24.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim GS, Park HJ, Woo JH, Kim MK, Koh PO, Min W, Ko YG, Kim CH, Won CK, Cho JH. Citrus aurantium flavonoids inhibit adipogenesis through the Akt signaling pathway in 3 T3-L1 cells. BMC Complement Altern Med. 2012;12:31.PubMedPubMed CentralGoogle Scholar
- Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol. 2010;88(1):33–9.PubMedView ArticleGoogle Scholar
- Yoshida H, Watanabe H, Ishida A, Watanabe W, Narumi K, Atsumi T, Sugita C, Kurokawa M. Naringenin suppresses macrophage infiltration into adipose tissue in an early phase of high-fat diet-induced obesity. Biochem Biophys Res Commun. 2014;454(1):95–101.PubMedView ArticleGoogle Scholar
- Jeon SM, Kim HK, Kim HJ, Do GM, Jeong TS, Park YB, Choi MS. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats. Transl Res. 2007;149(1):15–21.PubMedView ArticleGoogle Scholar
- Cho KW, Kim YO, Andrade JE, Burgess JR, Kim YC. Dietary naringenin increases hepatic peroxisome proliferators-activated receptor alpha protein expression and decreases plasma triglyceride and adiposity in rats. Eur J Nutr. 2011;50(2):81–8.PubMedView ArticleGoogle Scholar
- Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem. 2001;276(2):1486–93.PubMedView ArticleGoogle Scholar
- Xue B, Coulter A, Rim JS, Koza RA, Kozak LP. Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol. 2005;25(18):8311–22.PubMedPubMed CentralView ArticleGoogle Scholar
- Perez-Vizcaino F, Duarte J. Flavonols and cardiovascular disease. Mol Asp Med. 2010;31(6):478–94.View ArticleGoogle Scholar
- Stewart LK, Soileau JL, Ribnicky D, Wang ZQ, Raskin I, Poulev A, Majewski M, Cefalu WT, Gettys TW. Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6 J mice fed a high-fat diet. Metabolism. 2008;57(7 Suppl 1):S39–46.PubMedPubMed CentralView ArticleGoogle Scholar
- Jung CH, Cho I, Ahn J, Jeon TI, Ha TY. Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. Phytother Res. 2013;27(1):139–43.PubMedView ArticleGoogle Scholar
- Rivera L, Moron R, Sanchez M, Zarzuelo A, Galisteo M. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring). 2008;16(9):2081–7.View ArticleGoogle Scholar
- Moon J, Do HJ, Kim OY, Shin MJ. Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3 T3-L1 preadipocytes and the adipogenesis in high fat-fed rats. Food Chem Toxicol. 2013;58:347–54.PubMedView ArticleGoogle Scholar
- Dong J, Zhang X, Zhang L, Bian HX, Xu N, Bao B, Liu J. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. J Lipid Res. 2014;55(3):363–74.PubMedPubMed CentralView ArticleGoogle Scholar
- Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–60.PubMedPubMed CentralView ArticleGoogle Scholar
- Saito M. Capsaicin and related food ingredients reducing body Fat through the activation of TRP and brown Fat thermogenesis. Adv Food Nutr Res. 2015;76:1–28.PubMedView ArticleGoogle Scholar
- Kida R, Yoshida H, Murakami M, Shirai M, Hashimoto O, Kawada T, Matsui T, Funaba M. Direct action of capsaicin in brown adipogenesis and activation of brown adipocytes. Cell Biochem Funct. 2016;34(1):34–41.PubMedView ArticleGoogle Scholar
- Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol. 2016;173(15):2369–89.PubMedView ArticleGoogle Scholar
- Dinis P, Charrua A, Avelino A, Nagy I, Quintas J, Ribau U, Cruz F. The distribution of sensory fibers immunoreactive for the TRPV1 (capsaicin) receptor in the human prostate. Eur Urol. 2005;48(1):162–7.PubMedView ArticleGoogle Scholar
- Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, Anand P. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet. 2001;357(9265):1338–9.PubMedView ArticleGoogle Scholar
- Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288(5464):306–13.PubMedView ArticleGoogle Scholar
- Hong Q, Xia C, Xiangying H, Quan Y. Capsinoids suppress fat accumulation via lipid metabolism. Mol Med Rep. 2015;11(3):1669–74.PubMedGoogle Scholar
- Kawabata F, Inoue N, Masamoto Y, Matsumura S, Kimura W, Kadowaki M, Higashi T, Tominaga M, Inoue K, Fushiki T. Non-pungent capsaicin analogs (capsinoids) increase metabolic rate and enhance thermogenesis via gastrointestinal TRPV1 in mice. Biosci Biotechnol Biochem. 2009;73(12):2690–7.PubMedView ArticleGoogle Scholar
- Ohyama K, Nogusa Y, Shinoda K, Suzuki K, Bannai M, Kajimura S. A synergistic antiobesity effect by a combination of capsinoids and cold temperature through promoting beige adipocyte biogenesis. Diabetes. 2016;65(5):1410–23.PubMedView ArticleGoogle Scholar
- Yoneshiro T, Aita S, Kawai Y, Iwanaga T, Saito M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr. 2012;95(4):845–50.PubMedView ArticleGoogle Scholar
- Tamura Y, Iwasaki Y, Narukawa M, Watanabe T. Ingestion of cinnamaldehyde, a TRPA1 agonist, reduces visceral fats in mice fed a high-fat and high-sucrose diet. J Nutr Sci Vitaminol. 2012;58(1):9–13.PubMedView ArticleGoogle Scholar
- Jawale A, Datusalia AK, Bishnoi M, Sharma SS. Reversal of diabetes-induced behavioral and neurochemical deficits by cinnamaldehyde. Phytomedicine. 2016;23(9):923–30.PubMedView ArticleGoogle Scholar
- Giralt M, Cairo M, Villarroya F. Hormonal and nutritional signalling in the control of brown and beige adipose tissue activation and recruitment. Best Pract Res Clin Endocrinol Metab. 2016;30(4):515–25.PubMedView ArticleGoogle Scholar
- Iwasaki Y, Tanabe M, Kobata K, Watanabe T. TRPA1 agonists--allyl isothiocyanate and cinnamaldehyde--induce adrenaline secretion. Biosci Biotechnol Biochem. 2008;72(10):2608–14.PubMedView ArticleGoogle Scholar
- Masamoto Y, Kawabata F, Fushiki T. Intragastric administration of TRPV1, TRPV3, TRPM8, and TRPA1 agonists modulates autonomic thermoregulation in different manners in mice. Biosci Biotechnol Biochem. 2009;73(5):1021–7.PubMedView ArticleGoogle Scholar
- Han Y, Jung HW, Bae HS, Kang JS, Park YK. The extract of Cinnamomum cassia twigs inhibits adipocyte differentiation via activation of the insulin signaling pathway in 3 T3-L1 preadipocytes. Pharm Biol. 2013;51(8):961–7.PubMedView ArticleGoogle Scholar
- Abidov M, Ramazanov Z, Seifulla R, Grachev S. The effects of Xanthigen in the weight management of obese premenopausal women with non-alcoholic fatty liver disease and normal liver fat. Diabetes Obes Metab. 2010;12(1):72–81.PubMedView ArticleGoogle Scholar
- Maeda H, Hosokawa M, Sashima T, Takahashi N, Kawada T, Miyashita K. Fucoxanthin and its metabolite, fucoxanthinol, suppress adipocyte differentiation in 3 T3-L1 cells. Int J Mol Med. 2006;18(1):147–52.PubMedGoogle Scholar
- Kang SI, Ko HC, Shin HS, Kim HM, Hong YS, Lee NH, Kim SJ. Fucoxanthin exerts differing effects on 3 T3-L1 cells according to differentiation stage and inhibits glucose uptake in mature adipocytes. Biochem Biophys Res Commun. 2011;409(4):769–74.PubMedView ArticleGoogle Scholar
- Maeda H, Hosokawa M, Sashima T, Murakami-Funayama K, Miyashita K. Anti-obesity and anti-diabetic effects of fucoxanthin on diet-induced obesity conditions in a murine model. Mol Med Rep. 2009;2(6):897–902.PubMedView ArticleGoogle Scholar
- Maeda H, Hosokawa M, Sashima T, Funayama K, Miyashita K. Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. Biochem Biophys Res Commun. 2005;332(2):392–7.PubMedView ArticleGoogle Scholar
- Maeda H, Tsukui T, Sashima T, Hosokawa M, Miyashita K. Seaweed carotenoid, fucoxanthin, as a multi-functional nutrient. Asia Pac J Clin Nutr. 2008;17 Suppl 1:196–9.PubMedGoogle Scholar