A Review of Natural Stimulant and Non-Stimulant Thermogenic Agents

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PHYTOTHERAPY RESEARCH Phytother. Res. 30: 732–740 (2016) Published online 9 February 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5583

REVIEW A Review of Natural Stimulant and Non-stimulant Thermogenic Agents

Sidney J. Stohs1* and Vladimir Badmaev2 1School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA 2American Medical Holdings Inc., Staten Island, NY 10314, USA

Obesity and overweight are major health issues. Exercise and calorie intake control are recognized as the primary mechanisms for addressing excess body weight. Naturally occurring thermogenic plant constituents offer adjunct means for assisting in weight management. The controlling mechanisms for thermogenesis offer many intervention points. Thermogenic agents can act through stimulation of the central nervous system with associated adverse cardiovascular effects and through metabolic mechanisms that are non-stimulatory or a combination thereof. Examples of stimulatory thermogenic agents that will be discussed include ephedrine and caffeine. Examples of non-stimulatory thermogenic agents include p-synephrine (bitter orange extract), capsaicin, forskolin (Coleus root extract), and chlorogenic acid (green coffee bean extract). Green tea is an example of a thermogenic with the potential to produce mild but clinically insignificant undesirable stimulatory effects. The use of the aforementioned thermogenic agents in combination with other extracts such as those derived from Salacia reticulata, Sesamum indicum, Lagerstroemia speciosa, Cissus quadrangularis, and Moringa olifera,as well as the use of the carotenoids as lutein and fucoxanthin, and flavonoids as naringin and hesperidin can further facilitate energy metabolism and weight management as well as sports performance without adverse side effects. © 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd.

Keywords: thermogenesis; stimulant; non-stimulant; caffeine; ephedra; chlorogenic acid; p-synephrine; forskolin; green tea; capsaicin; flavonoids; carotenoids.

addition to promoting thermogenesis or via mechanisms that INTRODUCTION do not involve central nervous system (CNS) stimulation. Stimulants by definition are substances or agents that Thermogenesis is a process of converting nutrient calo- produce a temporary increase in the functional activity ries into the heat energy essential for body homeostasis, or efficiency of an organism or any of its parts. Some stim- that is, thermoregulation, maintaining healthy metabo- ulants not only activate the CNS but may also increase lism, and body weight control. Total energy expenditure thermogenesis and are therefore referred as stimulant includes energy required to perform cellular and organ thermogenics. Common indicators of CNS stimulatory ac- functions, energy expenditure induced by diet or cold tivity are increases in heart rate and diastolic and systolic exposure, and energy expenditure induced by physical blood pressure (Kassis et al., 2013). Non-stimulant thermo- activity. Twenty-four-hour energy expenditure (TEE) is genic agents enhance thermogenesis but do not produce the sum of resting energy expenditure (cardiorespiratory significant stimulation of the CNS and do not produce work and the work of maintaining transmembrane ion cardiovascular effects. gradients at rest; approximately 60% of TEE), the In general, vasoconstriction and an increase in blood thermic effect of feeding (the work of digestion; approx- pressure occur when ligands activate the noradrenergic – imately 5 10% of TEE), and non-resting energy expen- system or directly bind to α-1 adrenergic receptors resulting diture (energy expended in physical activity above in smooth muscle contraction in blood vessels, while – resting; approximately 30 40% of TEE). activation of α-2 adrenergic receptors in the CNS results Alterations in energy expenditure caused by diet or in reduced sympathomimetic activity. Activation of β-1 ad- ‘ cold exposure are often referred to as adaptive thermo- renergic receptors in the heart results in increased cardio- ’ genesis . Most models of obesity indicate defects in vascular contractility and increased heart rate, as well as adaptive thermogenesis and its regulation as an an increase in ghrelin secretion from the stomach, a important mechanism in maintaining healthy body hormone that promotes feeding mode. Binding to β-2 ad- composition and weight (Celi et al., 2015). Adaptive renergic receptors produces smooth muscle relaxation and thermogenesis can be modified by food and food is associated with bronchodilation. Binding of agonists to supplements. Potentiation of thermogenesis can be β-3 adrenergic receptors triggers thermogenesis and accomplished by substances that act as stimulants in results in the oxidation of fatty acids and production of energy (Inchiosa, 2011; Mund and Fishman, 2013). * Correspondence to: Sidney J. Stohs, 7068 Maumee Valley Court, Frisco, Stimulatory thermogenic agents as ephedrine exhibit TX 75034, USA. multiple mechanisms of action consisting of an indirect E-mail: [email protected] effect, which involves the release of norepinephrine Received 23 November 2015 Revised 11 January 2016 © 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd. Accepted 14 January 2016 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. STIMULANT AND NON-STIMULANT THERMOGENIC AGENTS 733 and epinephrine as well as a direct effect on adrenergic and the cell resumes its normal energy-conserving mode receptors. Through the indirect effect, norepinephrine storing ATP. UCP1 is an integral part of the inner and epinephrine act on α-, β-1, and β-2 adrenergic recep- mitochondria membrane and dissipates energy as heat tors to product the cardiovascular affects, while – an opposite mechanism to the ATP synthase, which interacting with β-3 adrenergic receptors to promote couples the energy inherent in the proton gradient to thermogenesis (Mund and Frishman, 2013). Ephedrine synthesis of ATP. The process of hydrolysis and also acts directly on all these adrenergic receptors to re-synthesis of cellular ATP is a continuous process produce thermogenesis and the associated undesirable facilitating thermogenesis or generating and storage of cardiovascular effects (Andraws et al., 2005; Diepvens ATP (Rosenbaum and Leibel, 2010). et al., 2007; Inchiosa, 2011). In the process of generating metabolic heat, as in Sympathomimetic agents vary broadly in their abilities adaptive thermogenesis, there are quantitative and to activate or inhibit various adrenergic receptors, and qualitative differences between the function of stimulant therefore, it should not be assumed that substances with and non-stimulant thermogenic supplements, with the some structural similarity will have similar effects former usually burdened with cardiovascular and CNS (Westfall and Westfall, 2014). For example, p-synephrine, side effects while the latter exert heat energy expendi- which is structurally similar to epinephrine, exhibits ture without the untoward biological effects. The differ- relatively little activation of α-, β-1, and β-2 adrenergic ence between stimulant and non-stimulant thermogenic receptors or upregulation of norepinephrine and epineph- action can be exemplified by the physiological role of rine, while exhibiting greater selective binding to β-3 insulin-mediated sympathetic stimulation in dietary ther- adrenergic receptors, thus promoting thermogenesis with- mogenesis. The physiological insulin increase with food out the unwanted cardiovascular effects (Stohs et al., intake leads to physiological sympathetic stimulation, in- 2011a). As a consequence, p-synephrine is an example of creased metabolic rate, the uncoupling mechanism, and a non-stimulatory thermogenic, which preferentially physiological thermogenesis. However, the association activates β-3 adrenergic receptors directly. of hyperinsulinemia with hypertension in the obese led The mechanisms involved in thermogenesis have many to the hypothesis that insulin-mediated excessive sympa- potential intervention and regulating points (Clapham, thetic stimulation may lead to thermogenesis as well as 2012). β-3 Adrenergic stimulation activates cellular the unintended consequence of increasing blood adenylyl cyclase, which leads to the conversion of adeno- pressure. The physiological reaction to food-induced sine triphosphate (ATP) to cyclic adenosine monophos- thermogenesis may exemplify non-stimulant thermo- phate (cAMP), activation of protein kinase A, and genic action, whereas persistent hyperinsulinemia phosphorylation and activation of triacylglycerol lipase. leading to high blood pressure may exemplify a stimu- The phosphorylated lipase converts triacylglycerols (white lant thermogenic action (Landsberg, 1996). storage fat) into free fatty acids, which act to release The UCP1 expression and thermogenesis may be uncoupling protein 1 (UCP1) by overriding the inhibition increased by non-stimulant nutritional thermogenics such caused by purine nucleotides (adenosine diphosphate as carotenoids, isoflavones, polyphenols, and flavonoids, (ADP), guanosine diphosphate (GDP), and adenosine which are discussed in the succeeding paragraphs. The triphosphate (ATP)) (Oelkrug et al., 2015). The UCP1- non-stimulant thermogenic compounds may safely ad- mediated uncoupling of the respiratory chain in mito- dress the ineffectual response in humans related to the chondria ultimately produces the metabolic heat or low number of β-3 adrenergic receptors and/or inducible thermogenesis (Fedorenko et al., 2012). How various brown adipocytes in human white fat (Poekes et al., thermogenic substances interact with this chain of meta- 2015). These compounds, which do not overstimulate bolic events will be described in the succeeding discussion. sympathetic receptors, may effectively assist in weight Uncoupling of the respiratory chain in mitochondria management and weight loss when used in conjunction is recognized as the main event leading to thermogene- with exercise and calorie intake control. sis and as such is targeted in pharmacologic and nutri- Various natural stimulant and non-stimulant thermo- tional intervention to upregulate thermogenesis. The genic substances are described in the succeeding para- role of the respiratory chain is to carry electrons with graphs with emphasis being placed on their mechanisms the increasing oxidation potentials, ultimately reducing of action. A detailed discussion of studies assessing effi- molecular oxygen to water. The energy generated in cacy of each of the substances described is beyond the that process is used to pump protons from the mitochon- scope of this review. The botanicals in this review were drial matrix into the intermembrane space, creating an selected based on available literature data indicating their electrochemical gradient known as the proton motive potential as thermogenic compounds. The purpose of the force, which activates the ATP synthase and drives the review is to highlight botanicals that have peer review conversion of ADP and inorganic phosphate (coupling data indicating thermogenic activity. reaction) to ATP (Rosenbaum and Leibel, 2010). Opposite to coupling, the activation of β-3 receptors by stimulant or non-stimulant thermogenic agents results in activation of UCP1. Incidentally, the superox- EXAMPLES OF NATURAL THERMOGENIC ide or peroxidation products generated in the respira- AGENTS tory chain can also activate (unlock) the UCP1. Subsequently, the activated UCP1 uncouples the respi- Ephedrine ratory chain, allowing rapid fatty acid oxidation with a low rate of ATP production and high ATP utilization Ephedrine is a phenylpropylamine protoalkaloid and heat energy release, hence, thermogenesis. derived from the shrub Ephedra sinica. It is a sympatho- At the termination of thermogenesis, the mitochon- mimetic agent that acts both as a stimulant and a dria oxidize the residual fatty acids, UCP1 is inactivated, thermogenic. The ability of ephedrine to enhance

© 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd. Phytother. Res. 30: 732–740 (2016) 734 S. J. STOHS AND V. BADMAEV energy expenditure and promote weight loss has been 1990; Donovan and DeVane, 2001; Nawrot et al., 2003). demonstrated in a number of human studies (Astrup, Typical doses of caffeine are in the range of 100–150 mg 2000; Diepvens et al., 2007). Ephedrine mediates these two to three times daily, with daily doses up to 400 mg effects by several mechanisms. It enhances the sympa- being considered safe and without serious adverse effects thetic neuronal release of norepinephrine and epineph- (European Food Safety Authority, 2015). rine with subsequent excitatory effects on the cardiovascular system via α-1, α-2, and β-1 adrenergic receptor stimulation (Diepvens et al., 2007). Abuse of p-Synephrine ephedra and ephedrine by the use of indiscriminately high doses resulting in cardiovascular adverse events p-Synephrine is a phenylethylamine derivative obtained as an increase in blood pressure, tachycardia, insomnia, from the dried immature fruits of Citrus aurantium (bitter and restlessness has resulted in the removal of these orange) and is also present in other citrus species as products from the market. An effective thermogenic mandarin oranges, clementine, and Marrs sweet oranges. dose of ephedrine is about 20 mg twice daily with a The patented extract of bitter orange, which is standard- low probability of adverse events (Hackman et al., ized to p-synephrine, is known as Advantra Z® or ™ 2006). Kinetiq . p-Synephrine has some structural similarities Ephedrine is believed to stimulate thermogenesis via to ephedrine, norepinephrine, and epinephrine. However, interaction with β-3 adrenergic receptors, resulting in because of the structural differences, p-synephrine the breakdown of fats and modulation of glucose metab- exhibits markedly different adrenergic receptor binding olism (Liu et al., 1995; De Matteis et al., 2002; Carey properties. Because p-synephrine exhibits little or no et al., 2015) as well as an indirect mechanism involving binding to α-1, α-2, β-1, and β-2 adrenergic receptors as the release of norepinephrine and epinephrine from opposed to ephedrine (Stohs et al., 2011a), cardiovascular synaptic nerve endings, which interact with adrenergic effects as an increase in heart rate and blood pressure are receptors (Inchiosa, 2011). Ephedrine also inhibits not observed at commonly used doses (Stohs and Preuss, monoamine oxidase and thus slows the degradation of 2011; Stohs et al., 2011b, 2012a, 2012b; Stohs and Shara, norepinephrine. Some of the thermogenic effects may 2013). Therefore, p-synephrine cannot be classified as a also be mediated by interaction of ephedrine with β-1 stimulant. and β-2 adrenergic receptors (Liu et al., 1995). The p-Synephrine exerts its effects through multiple thermogenic effect of ephedrine can be potentiated by biochemical mechanisms. It enhances thermogenesis the concurrent use of caffeine as the result of comple- by binding to β-3 adrenergic receptors, resulting in an mentary mechanisms (Astrup, 2000; Ray et al., 2005; increase in the body’s ability to breakdown fats, which Hackman et al., 2006; Diepvens et al., 2007). are further metabolized to produce energy (Carpene’ et al., 1999, 2014; Mercader et al., 2011). p-Synephrine also enhances carbohydrate metabolism (Hong et al., Caffeine 2012; Peixoto et al., 2012; de Oliveira et al., 2014). p-Synephrine facilitates cellular uptake of glucose in Caffeine is the world’s most widely consumed stimulant muscle cells, as well as glycogenolysis, gluconeogenesis, and has various effects and mechanisms of action. In glycolysis, and oxygen uptake. The involvement of both vascular smooth muscle cells, caffeine acts predomi- calcium ion and cAMP along with adrenergic receptors nantly as a competitive inhibitor of the enzyme phos- were demonstrated to be involved in these biochemical phodiesterase, which is responsible for the breakdown processes (de Oliveira et al., 2014), indicating the of 3 ,5 -cAMP. cAMP is one of the most important involvement of multiple mechanisms. second messengers in mammalian cells and is responsi- Typical doses of p-synephrine (as Advantra Z and ™ ble for diverse signaling responses including those Kinetiq ) are in the range of 30–50 mg two to three responsible for energetic status (AMP/ATP ratio) and times daily (Kaats et al., 2013). In summary, the effects of caffeine and coffee (Montoya et al., 2014; p-synephrine is an example of a non-stimulant thermo- Nunes et al., 2014). genic agent. No serious adverse events have been A second mechanism of action of caffeine is based on directly attributed to p-synephrine or bitter orange its binding to and inhibiting adenosine A1 and A2a extract (Stohs and Preuss, 2011; Stohs et al., 2011b, receptors (Benowitz, 1990; Donovan and DeVane, 2012b; Stohs and Shara, 2013). 2001; Nawrot et al., 2003). Inhibition of the A1 receptor The citrus-derived bioflavonoids naringen and/or by caffeine results in activation of adenylate cyclase with hesperidin or their aglycones have been shown in vari- a subsequent increase in cAMP and in the activity of ous animal experiments to improve insulin sensitivity protein kinase A, the latter being associated with stimu- and glucose tolerance, prevent biosynthesis and accu- lation of the CNS. mulation of triglycerides, inhibit cholesterol biosynthe- The resultant downstream pharmacological effects sis, and serve as antioxidants and anti-inflammatory include an increase in energy metabolism, decrease in agents with a decrease in inflammatory markers smooth muscle contraction, vasodilatation, and in (Mulvihill et al., 2009; Goldwasser et al., 2010). A study neurotransmitter release resulting in CNS stimulation, has shown that the combination of p-synephrine with positive inotropic (and possibly weak chronotropic) these two bioflavonoids enhances thermogenesis with- effects on the heart, vasoconstriction, and increased out adverse cardiovascular effects (Stohs et al., 2011c). blood pressure. Some people experience insomnia in A single dose of p-synephrine (50 mg) in human subjects response to caffeine. In addition, in the kidney, caffeine exhibited a 65 kcal increase in resting metabolic rate induces diuresis, vasodilatation and sodium reabsorp- (RMR) relative to the placebo group (24 h energy tion in response to an increased glomerular filtration expenditure). In the group receiving p-synephrine plus rate because of increased blood pressure (Benowitz, naringin and hesperidin, the RMR increased by

183 kcal, an increase that was statistically significant et al., 2007; Westerterp-Platenga, 2010; Turkozu and with respect to the placebo control. Thus, the combina- Acer Tek, 2015). The constituents responsible are tion of p-synephrine with the bioflavonoids offers multi- believed to be caffeine and catechins including epicate- ple mechanisms for increasing energy expenditure chin, epicatechin gallate, epigallocatechin, and epigallo- without adverse stimulant effects. catechin gallate (EGCG), with EGCG being the most abundant (50–80%) and most potent. The amount of caffeine in a cup (250 mL) of green tea may be in the Capsaicin and capsiate range of 15–100 mg, depending on the manner in which the tea is prepared. The effects of caffeine on energy Hot red peppers (Capsicum species) contain pungent expenditure and thermogenesis have been described compounds called capsaicinoids with capsaicin being earlier. In general, the amount of caffeine to which an the major pungent principle. Capsiate is a non-pungent individual is exposed via green tea or green tea extracts analog of capsaicin derived from a ‘sweet’ pepper, which is much less than through coffee consumption or where has been demonstrated to have thermogenic properties caffeine is directly used in a product. similar to those of capsaicin (Ludy et al., 2012). Capsiate The catechins in green tea are believed to influence may prove to be of greater utility with respect to ther- energy expenditure through inhibition of the enzyme mogenesis and weight management because it can be catechol-0-methyl transferase (Diepvens et al., 2007; given at effective doses without the pungent, burning Westerterp-Platenga, 2010; Turkozu and Acer Tek, characteristics of capsaicin, and therefore may exert 2015). This enzyme is responsible for the degradation fewer adverse effects. Typical human doses of capsaicin of catecholamines including norepinephrine. Because are in the range of 30–150 mg per day (Ludy et al., 2012). the degradation of norepinephrine and epinephrine To date, most studies regarding thermogenesis have are slowed, continuous stimulation of adrenergic recep- been conducted with capsaicin. tors occurs with a resultant increase in energy expendi- Multiple mechanisms exist with respect to the actions ture and fat oxidation. As a consequence, the data of capsaicin, which may account for the observations that indicate that the thermogenic effects of green tea and it acts as a thermogenic agent without causing stimulant green tea extracts are due to a combination of mecha- and adverse cardiovascular effects (Ludy et al., 2012; nisms associated with caffeine and catechins. In general, Janssens et al., 2013; Yoneshiro and Saito, 2013; McCarty green tea extracts produce mild stimulatory effects that et al., 2015). Capsaicin has been shown to stimulate the result in clinically insignificant cardiovascular effects release of the catacholamines norepinephrine and epi- (Diepvens et al., 2007). nephrine from the adrenal medulla (Reinbach et al., Green tea is widely consumed, and in general, its con- 2010; Ludy et al., 2012), which in turn promote thermo- sumption is considered to be very safe and associated genesis through their actions on adrenergic receptors. with health benefits because in part of its antioxidant ac- However, capsaicinoids also have the potential to tivity. However, on rare occasions, cases of hepatotoxic- modulate metabolism through their activation of tran- ity have been reported, particularly when green tea is sient receptor potential vanilloid 1 receptors where they consumed in large amounts (Mazzanti et al., 2009). are also believed to be able to increase energy expenditure and decrease body fat by enhancing catabolic processes in adipose tissues (Yoneshiro and Saito, 2013; Forskolin McCarty et al., 2015). Activation of these vanilloid receptors also causes vasodilatory responses believed to occur Forskolin is a diterpene derived from the roots of the through activation of nitric oxide synthase and induction plant Coleus forskohlii. It has long been known to be of calcium fluxes (McCarty et al., 2015). As a conse- an effective activator of the enzyme adenylate cyclase quence, cardiovascular effects as an increase in heart (Insel et al., 1982), which is responsible for the forma- rate and blood pressure because of capsaicin-induced tion to cAMP. Initial studies were conducted in human release of the catacholamines is counteracted, and capsa- platelet membranes. As described earlier, cAMP serves icin therefore acts as a non-stimulant thermogenic. as a second messenger with numerous functions. Adverse effects associated with capsaicin are primar- Forskolin (Forslean®) via cAMP may affect body ily related to its direct irritation of the eyes, mucus metabolism and body fat by increasing lean body mass membranes, and respiratory tract (Copeland and and metabolic activity (Badmaev et al., 2002). cAMP Nugent, 2013; Srinivasan, 2015). If ingested in large elevating agents as forskolin induce thermogenesis only amounts, capsaicin can cause nausea, vomiting, abdom- through the beta-receptors and the resulting increase in inal pain, and burning diarrhea (Srinivasan, 2015). cAMP levels (Zhao et al., 1997). Forskolin per se does Although case studies have suggested a link with not stimulate beta-receptors. Typical human doses of adverse cardiovascular events when consuming red forskolin are in the range of 10–25 mg twice daily with pepper (Sayin et al., 2012), no adverse effects have ever C. forskohlii extracts being most commonly standard- been shown to be directly associated with capsaicin, and ized to 10% forskolin. No studies have examined the various studies have indicated cardioprotective and long-term effects of forskolin at these doses. chemoprotective effects (Srinivasan, 2015). Various studies have shown that forskolin (Forslean) can decrease fat mass in humans and do so without significant effects on the cardiovascular system Green tea (Badmaev et al., 2002; Godard et al., 2005). Furthermore, forskolin (C. forskohlii extract) has been shown to work Various studies have indicated that consumption of synergistically with extracts of Salacia reticulata and green tea and green tea extracts can increase thermo- Sesamum indicum in formula FB3® to inhibit pancreatic genesis and fat oxidation (Dulloo et al., 2000; Diepvens lipase and prevent dietary fat absorption (Badmaev

© 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd. Phytother. Res. 30: 732–740 (2016) 736 S. J. STOHS AND V. BADMAEV et al., 2015). Thus, the ability of this combination of in- (PPAR) γ that is responsible for adipogenic gene gredients to decrease body fat may primarily involve a expression (Maeda, 2015). combination of mechanisms including inhibition of pancreatic lipase. Isoflavones

Chlorogenic acid Isoflavones, abundant in legumes as soy, red clover, and kudzu, are polyphenolic compounds that exert biologi- Chlorogenic acid is the major hydroxycinnamic acid cal effects similar to estrogens. They are classified as derivative present in green coffee beans. Human and phytoestrogens or plant-derived compounds with estro- animal studies have shown that chlorogenic acid and genic activity. Isoflavones are present in nature as glyco- – green coffee bean extracts (45 55% chlorogenic acid) sides (bound to a sugar molecule) or a digested form enhance energy metabolism and expenditure, decrease released of the sugar molecule leaving an isoflavone blood lipid levels, improve glucose tolerance, and aglycone. Genistin, daidzin, and glycitin are examples support weight management without cardiovascular of isoflavone glycosides, while the aglycones are called effects. Typical human doses are in the range of genistein, daidzein, and glycitein, respectively. The – 300 400 mg of the extract two to three times daily biological effects of isoflavones depend on their metab- (Onakpoya et al., 2011; Cho et al., 2010; Ho et al., 2012; olism, which in turn depends on the activity of gastroin- Ma et al., 2015). No studies have examined the long- testinal bacteria. For example, isoflavone daidzein may term effects of green coffee bean extracts or chlorogenic be metabolized in the intestine to equol, a metabolite acid at these doses. that has greater estrogenic activity than daidzein. Several mechanisms of action appear to be involved. Studies that measure urinary equol excretion after soy Chlorogenic acid and the related hydroxycinnamic acid consumption indicate that only about 33% of individ- analogs cinnamic acid and ferulic acid have been shown uals from Western populations metabolize daidzein to to inhibit cAMP phosphodiesterase, which results in equol (Zheng et al., 2013; Franke et al., 2014). Thus, upregulation of adenosine monophosphate activated individual differences in the metabolism of isoflavones protein kinase (AMPK), a key sensor of energy metabo- could be decisive in use of those compounds as thermo- lism, with a resultant increase in fatty acid oxidation genic food supplements. (Bruckbauer and Zemel, 2014). A supporting mechanism Other examples of isoflavones enhancing energy that contributes to the weight management effects is the metabolism exist. Extracts of kudzu flowers in a crude inhibition of the enzyme pancreatic lipase, which results form or with isoflavone-rich fraction fed with a high- in a decrease in lipid absorption (Narita et al., 2012). fat diet to C57BL/6 J mice for 42 days prevented statistically significantly adiposity and development of fatty Carotenoids liver. Kudzu fed groups also exhibited significant increases in oxygen consumption and UCP1-positive Carotenoids are pigments with anti-oxidant activity and brown adipose tissue (Kamiya et al., 2012). with potential to convert to vitamin A. Chemically carot- Fourteen-day treatment with daidzein (50 mg/kg) of enoids are tetrapenoid compounds divided into groups obese rats on a high-fat diet reduced weight gain and of carotenes, which are hydrocarbons with no oxygen in fat content in the liver, accompanied by high leptin the molecule, and xanthophylls, which are hydrocarbons and low adiponectin levels in plasma. Both adipose with oxygen in the molecule. Carotenes include tissue and the liver showed marked changes after treat- beta-carotene, alpha-carotene, beta-cryptoxanthin, and ment with daidzein, affecting transcription factors and gamma-carotene, which besides being anti-oxidants can lipogenic enzymes, particularly stearoyl coenzyme A be converted in the body to vitamin A. Xanthophylls in- desaturase 1 – considered a pivotal enzyme in obesity. clude lutein, astaxanthin, zeaxanthin, and fucoxanthin Expression of UCP1, an important enzyme for thermo- and play important roles as antioxidants. The effect of genesis, was increased in brown adipose tissue after carotenoids on brown adipocyte proliferation in mice daidzein treatment (Crespillo et al., 2011). and differentiation in tissue culture has shown that beta- An isoflavone-rich ethanolic extract of sea buckthorn carotene, alpha-carotene, and lutein can enhance the fed to C57BL/6 J mice on high-fat diet for 13 weeks expression of mitochondrial UCP1 expression in a dose- significantly reduced the food intake, body weight gain, dependent manner. The carotenoids with provitamin A epididymal fat pad weight, hepatic triglyceride content, activity had the most potential to affect the expression of hepatic, and serum total cholesterol levels and serum UCP1 and enhance thermogenesis. (Serra et al., 1999). leptin levels. The hepatic mRNA expression of PPARα The xanthophyll fucoxanthin, a major carotenoid found and carnitine palmitoyl transferase 1 along with PPARγ in edible brown seaweeds, has the ability to increase resting were significantly increased, whereas the level of acetyl- energy expenditure by induction of UCP1 (Maeda, 2015). CoA carboxylase was significantly reduced with the sea Furthermore, fucoxanthin has been shown to upregulate buckthorn regimen (Pichiah et al., 2012). UCP1 gene expression in white adipose tissue, which then contributes to the reduction in white adipose tissue and overall body weight in mice. Maeda and associates (2015) Flavonoids also demonstrated that fucoxanthin inhibited glycerol-3- phosphate dehydrogenase activity, which suppressed Flavonoids are polyphenolic plant pigments with a adipocyte differentiation and lipid accumulation, and was versatile biological role as chemical messengers, physio- associated with lower body mass index, fat mass, and logical regulators, and cell cycle inhibitors. They can be fasting blood glucose. That study also revealed a downreg- classified into flavonoids or bioflavonoids, isoflavonoids, ulation of the peroxisome proliferator-activated receptor and neoflavonoids.

Citrus flavonoids, including naringenin, hesperetin, known for years that carotenoids exhibit thermogenic nobiletin, and tangeretin, have emerged as promising activities that involve altered carbohydrate and lipid therapeutic agents for the treatment of metabolic metabolism without cardiovascular effects (Serra et al., dysregulation. In animal models, citrus flavonoid supple- 1999; Muriach et al., 2008; Maeda, 2015). Examples of ments prevent hepatic steatosis, dyslipidemia, and insu- carotenoids that may modulate energy metabolism lin sensitivity primarily through inhibition of hepatic include lutein, β-carotene, zeaxanthin, lycopene, and fatty acid synthesis and increased fatty acid oxidation astaxanthin (McNulty et al., 2008). (Mulvihill et al., 2009). Citrus flavonoids blunt the Various other plant extracts may enhance thermogen- inflammatory response in metabolically important esis when combined with well-known thermogenic tissues including liver and adipose tissue, which may agents. Studies have shown that aqueous extracts of S. prevent obesity (Alam et al., 2014; Parhiz et al., 2015). reticulata modulate glucose and lipid metabolism The citrus flavonoid naringenin is one of the most through multiple mechanisms (Stohs and Ray, 2015). abundant citrus flavonoids. Particularly in its aglycone Extracts of the seeds of S. indicum have also been shown form, naringenin, which also exists in a glycosidic form to modulate lipid metabolism (Biswas et al., 2010; naringin, has been shown in vitro to regulate steps in Asgary et al., 2013). As noted earlier, the combination carbohydrate and lipid metabolism. Naringenin may of forskolin with extracts of S. reticulata and S. indicum target transcriptional regulation of metabolism through (FB3) have been shown to work synergistically with nuclear receptors, a family of ligand-activated transcrip- respect to prevention of dietary fat absorption decreas- tion factors. The flavonoid inhibits adipocytes differenti- ing body fat content (Badmaev et al., 2015). ation and may induce in vitro the fatty acid oxidation Extracts of Lagerstroemia speciosa (banaba) have genes including the UCP1 as well as PPAR-regulated been shown to enhance glucose and lipid metabolism genes for CYP4A11, acyl-CoA oxidase, and apolipopro- in both humans and animals (Stohs et al., 2012a). teins (Mulvihill et al., 2009; Goldwasser et al., 2010). Corosolic acid is believed to be the primary active agent Naringin is widely distributed in citrus species and other in banaba with effects being mediated through a variety plants. Rat studies have shown that exceedingly high of signal transduction mechanisms. Similarly, extracts of doses are without toxic effects. The no-observed-ad- the leaves of Moringa oleifera enhance metabolism of verse-effect level of naringin in rats was shown to be glucose and lipids, presumably through a wide variety greater than 1250 mg/kg/day when administered orally of polyphenolic constituents (Stohs and Hartman, for 13 weeks (Li et al., 2013). 2015). Extracts of Cissus quadrangularis represent an- Cocoa beans and by extension chocolate-contained other example of a plant extract that offers potential flavan-3-ols have been credited with enhancing meta- for enhancing thermogenesis when combined with other bolic activity and preventing obesity. In an in vivo study, well-known thermogenic agents (Stohs and Ray, 2013). a mixture of flavan-3-ols administered to mice signifi- Administration of punicic acid, the primary fatty acid cantly enhanced systemic energy expenditure, as present in pomegranate seed oil, has been shown to evidenced by an accompanying increase in the type of significantly reduce white adipose tissue in rats and gene expression responsible for thermogenesis and lipol- suppress the production and secretion of triglycerides ysis. By comparison, a tea that contained polyphenols and apolipoprotein B100 (Arao et al., 2004a, 2004b). Lai exhibited less metabolic activity. The uncoupling pro- et al. (2012) investigated the effects of fucoxanthin com- tein1 (UCP-1) and PPARγ coactivator-1 alpha (PGC-1α) bined with pomegranate seed oil standardized for punicic in brown adipose tissue were significantly increased 2 h acid in a compound formula (Xanthigen®). The combina- after administration of cocoa flavonoids to mice tion of these two supplements suppressed accumulation of (Matsumura et al., 2014). Flavan-3-ols derived from lipid droplets in adipocytes, downregulated PPARγ,cyto- cocoa fed to rats maintained on high-fat diet for 4 weeks sine-cytosine-adenosine-adenosine-thymidine (CCAAT)/ showed epididymal adipose tissue weight significantly enhancer binding protein, and fatty acid synthase. lower with the UCP1 in brown adipose tissue, and Abidov et al. (2010) conducted a human trial examin- UCP3 in gastrocnemius significantly increased. The ing the effects of Xanthigen in soft gelatin capsules nutritional flavan-3-ols may reduce white adipose tissue containing 100 mg pomegranate seed oil (70% punicic and weight gain by enhancing thermogenesis and lipoly- acid) and 100 mg of brown sea weed extract (0.8% fuco- sis (Osakabe et al., 2014). xanthin). Subjects had either normal liver fat content or had non-alcoholic fatty liver disease (NAFLD). Sixteen weeks of 200 mg of Xanthigen supplementation three Combination products times daily resulted in significant loss of body mass, body fat, and liver fat and decreased systolic and dia- Examples of the use of combinations of herbal ingredients stolic blood pressure, serum triglyceride levels, and to enhance thermogenesis are presented in the succeeding C-reactive protein levels in both the normal liver fat discussion. The addition of the flavonoids naringin and and NAFLD groups as compared with placebo. hesperidin enhance the non-stimulant thermogenic effect An additional interesting observation from the clini- of p-synephrine (as Advantra Z) (Stohs et al., 2011c). Caf- cal study of Xanthigen is the change in the respiratory feine when combined with p-synephrine (as Advantra Z) quotient (RQ) in the Xanthigen versus placebo group. with respect to sports performance has been shown to A decrease in RQ (towards 0.7) indicates a shift in significantly increase mean power and velocity of squat substrate metabolism to a greater dependence upon performance, suggesting an enhanced thermogenic effect fat. The RQ also known as respiratory exchange ratio (Ratamess et al., 2015). (RER) is an index of the body’s metabolic activity. The combination of carotenoids and isoflavones with Typically, when an individual is utilizing 100% carbohy- other thermogenic agents offers great potential to drate as a fuel for energy, the RER is 1.0. For fats, the enhance and facilitate energy metabolism. It has been RER is approximately 0.7. For a starving individual,

© 2016 The Authors Phytotherapy Research published by John Wiley & Sons Ltd. Phytother. Res. 30: 732–740 (2016) 738 S. J. STOHS AND V. BADMAEV the RER may be as low as 0.7, reflecting utilization of non-stimulant thermogenic because of its pungency. body fat, which in starvation often co-exists with lean The non-pungent analog capsiate may prove to be more body mass wasting. This shift is commonly observed in useful. Green tea extracts exhibit stimulant thermogenic stimulatory thermogenic weight-loss supplements such activity while producing clinically insignificant increases as caffeine and ephedra (Vukovich et al., 2005; Jitomir in heart rate and blood pressure because of a combina- et al., 2008) and has been associated with cardiovascular tion of mechanisms. side effects such as an increased blood pressure. There- In recent years, a wide variety of plant extracts as well fore, potential for non-stimulant thermogenic com- as isolated carotenoids and flavonoids have been shown pounds or combinations thereof which shift metabolism to exhibit beneficial effects with respect to lipid and towards fat utilization and without ‘starvation’ or cardio- carbohydrate metabolism and do so without adverse vascular effects is highly valuable in the nutritional field effects. Examples include extracts of S. reticulata, S. and offers much promise. indicum, L. speciosa (banaba), C. quadrangularis, and M. oleifera. These plant extracts when used in combination with well-known thermogenic agents offer great potential for enhancing energy metabolism and produc- DISCUSSION AND SUMMARY tion without adverse effects. Potential benefits of various combination products include weight loss and Weight-related health issues are a major concern world- weight management, increased alertness and energy, wide. Overweight and obesity are associated with and enhanced sports performance. increased risks for heart diseases, strokes, hypertension, Finally, comparing effects of thermogenic botanicals diabetes, many forms of cancer, and other disease states. to the effects of exercise induced thermogenesis are The most straight-forward approach to weight manage- appropriate because ultimately those two different ment and weight control is calorie intake control and approaches trigger the similar biochemical events lead- greater calorie expenditure through exercise and physi- ing to increases in thermogenesis and energy expendi- cal activities. However, the majority of people fail in ture. The energy expenditure due to food consumption, their attempts to do so. As a consequence, much interest cold exposure, or exercise ultimately has a common exists in nutrients and supplements that may facilitate denominator, that is, thermogenesis. However, it should calorie utilization, satiety, and weight loss. A wide vari- be noted that although increases in thermogenesis are ety of plant-derived substances offer great potential for mechanistically similar, they are smaller when contrib- assisting with weight loss and weight management. uted exclusively by botanicals versus that which can be However, it should be kept in mind that while these achieved through exercise. Furthermore, exercise can plant-derived substances may assist with weight loss stimulate cellular protein synthesis leading to height- and weight management, they do not guarantee long ened energy expenditure and increased muscle mass, lasting effects, which must be based on lifestyle changes. effects not reported following the use of the thermogenic Both natural stimulant and non-stimulant ingredients botanicals summarized in this report. The US National exist, with the non-stimulant agents providing enhanced Institutes of Health guidelines for evaluation of weight thermogenesis without CNS stimulation and the associ- loss compounds versus placebo typically include ated adverse cardiovascular effects as an increase in balanced diet and daily physical activity in both study heart rate and blood pressure. Typical stimulant ther- groups. To date, proper clinical research proving or mogenic substances include ephedrine and caffeine, disproving the usefulness of most thermogenic botanicals with ephedrine being generally banned because of the in weight management is lacking (Bahmani et al., 2015). reported high incidence of adverse effects when used However, their thermogenic mechanisms of natural non- at doses higher than recommended, while caffeine is stimulant botanical products constitute a basis for further the worlds most consumed stimulant. investigation of their potential in weight loss and weight Examples of non-stimulant thermogenic substances management. include p-synephrine (bitter orange extracts), forskolin (C. forskohlii extracts), chlorogenic acid (green coffee bean extracts), and capsaicin. Although p-synephrine is Conflict of Interest structurally related to ephedrine, because of structural The authors have served as consultants for Novel Ingredients, a com- differences, it exhibits little binding to α-, β-1, and β-2 pany that markets various thermogenic ingredients as well as other adrenergic receptors that are responsible for cardiovas- herbal products. No funds were received by the authors in support of cular effects. Capsaicin is limited in its value as a this review.

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