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For citation purposes: Ambati S. Garlic derivatives: role in obesity and related disorders. OA Biotechnology. 2013 Jan 14;2(1):1.
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Critical review
* Corresponding authorEmail: [email protected] Department of Animal and Dairy Science, 448
Edgar L. Rhodes Center for Animal and Dairy Science, University of Georgia, Athens, GA 30602-2771, USA
Introduction
DiscussionThe author has referenced some of its own studies in this review. The protocol of these studies have been approved by the relevant ethical co-mmittee related to our institution in which it was performed.
Garlic compounds: chemistryTwo classes of organosulphur comp-ounds are derived from garlic: (1) li-pid-soluble (Figure 2a) and (2) wat-er-soluble (Figure 2b) allyl sulphur compounds. Lipid-soluble sulphur c-ompounds are formed from its pare-nt sulphur compound, alliin, which c-onstitutes about 80% of the cysteine sulphoxides in garlic. Lipid-soluble allyl sulphur compounds such as ajo-ene, diallyl sulphide (DAS), diallyl di-sulphide (DADS) and diallyl trisulph-ide (DATS) are released from alliin catalysed by alliinase enzyme, which is released by either chopping or cr-ushing garlic. Water-soluble allyl sul-phur compounds, such as S-allyl cys-teine (SAC) and S-allyl mercaptocys-teine, are obtained during long-term incubation of crushed garlic in aqu-eous solutions in the ageing process.
Garlic organosulphur compounds and adipogenesisSeveral organosulphur compounds have shown inhibitory effects on adi-pogenesis11,12. They reduce the synt-hesis of lipids in 3T3-L1 adipocytes4 and human adipocytes5. In addition to this, some of
AbstractIntroduction
Garlic derivatives: role in obesity and related disordersS Ambati1*
Med
ical
Bio
tech
nolo
gy
For centuries, garlic has been used for culinary and remedial purposes. In recent years, plant-based chemic-als have been extensively explored for their potential as nutraceuticals in the treatment of various health conditions. Garlic-derived organosu-lphur compounds with anti-oxidant and anti-inflammatory properties can relate to incredible beneficial eff-ects in treating various cancer condi-tions in in vitro and in vivo models. Some garlic compounds have the po-tential to inhibit adipocyte prolifera-tion and differentiation, and they re-duce their number by apoptosis. Bo-th adipocytes and bone-forming ost-eoblasts arise from a common precursor, mesenchymal stem cells. Because of this common lineage, the-re exists a direct relationship betwe-en obesity and osteoporosis, especi-ally in post-menopausal females. Ga-rlic and its compounds have proven to be beneficial in reducing adiposity and improving bone health in rode-nts. This critical review discusses the role of garlic derivatives in obesity and related disorders.ConclusionGarlic and its derivatives hold prom-ise in the development of therape-utics to address problems of obesity and associated health conditions.
developing countries. According to the latest data from National Health and Nutrition Examination Survey, more than one-third of adults and al-most 17% of youth were obese in the USA in 2009–2010, and the prev-alence levels did not differ between adult men (35.5%) and women (35.8%)1. The problem of obesity is compounded by its involvement in a multitude of disorders including, but not limited to insulin resistance, ty-pe 2 diabetes, osteoporosis, cardiov-ascular diseases, cancer, etc. These manifestations are the result of imp-aired adipose tissue metabolic activity that contributes to altered endocrine function. The incidence of obesity is due to an increase either in the adipocyte number (hyperplasia) and/or in the volume of a typical adipocyte (hype-rtrophy)2. Moreover, there is a turn-over of fat cells throughout life und-er different sets of conditions, which may result in obesity. Pharmaceutic-al remedies formulated to alleviate the problem of obesity, which are currently available, are associated with undesirable side effects. Efforts to explore non-pharmaceutical ther-apeutic approaches have since gro-wn and much of such focus has been on natural products in general and phytochemicals in particular. Garlic derivatives are one such potential cl-ass of phytochemicals that can prod-uce promising results in therapy and are capable of providing a number of other health benefits. A wealth of in-formation is available showing bene-ficial effects of garlic derivatives su-ch as anti-adipogenic, anti-inflamm-atory, antioxidant, anti-cancer, anti-mutagenic, anti-microbial, anti-hyp-erlipidaemic, anti-viral and other ad-ditional properties3–10 (Figure 1). While the therapeutic action of garl-
ic compounds in cancer treatment h-as generated a lot of interest and re-search, the anti-adipogenic potential has not been explored much. This cr-itical review explores anti-adipogen-ic potential of garlic compounds.
Obesity has assumed alarming prop-ortions, and its incidence is increasi-ng worldwide both in developed and
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For citation purposes: Ambati S. Garlic derivatives: role in obesity and related disorders. OA Biotechnology. 2013 Jan 14;2(1):1.
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Critical review
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and markers; in differentiating cells, acetyl coA-carboxylase1, an essen-tial component in fatty acid synthesis and metabolism, has been lowered through AMPK activation4. Inhibition of adipogenesis through abolition of inflammatory molecule secretion (IL-6 and MCP-1) and reduced expres-sion of adipogenic factors/genes such as PPARγ, CEBPα, lipoprotein lipase (LPL) and adiponectin by 1,2-vinyl-dithiin in differentiating human pre-adipocytes is another example to substantiate anti-adipogenic proper-ties of organosulphur compounds of garlic5. In contrast, DADS accelerated terminal differentiation of 3T3-L1 cells into adipocytes through inhibit-ing histone deacetylase, increasing the expression of adipogenesis-related LPL, FAS, SREBP1c, aP2 and PPARγ and lowering the expression of pref-1, a preadipocyte marker14.
Structure–activity relationships Structure–activity relationships are not only critical in explaining the chemical nature and functional rela-tionships of the compounds but are also indicators of the type of activ-ity/reaction that they can elicit in target biological systems. Thiols, sulphur-containing structures, are important components of all biologi-cal systems and are essential for life. Organosulphur compounds of gar-lic have either one or more sulphur atoms, through which they, at least in part, exert their biological activ-ity15. In addition to the number of sulphur atoms, types of alk(en)yl groups are activity-determining fac-tors16. Although allyl groups appear to induce growth arrest in cancer cells, all allyl compounds are not equally potent. Lipid-soluble allyl sulphur compounds such as DADS and DATS are more effective than water-soluble allyl sulphur compounds such as SAC. The anti-oxidant property of garlic derivatives stems from their ability to scavenge free radicals and offer pro-tection to cellular membrane from various assaults, and at the same time,
these compounds are able to decrease cell viability and are implicated in influencing the adipocyte number12. Such suppression in adipocyte viabil-ity was reportedly caused by ajoene-induced apoptosis. Ajoene is more potent on adipocytes when compared to several other garlic organosulphur compounds; in addition, ajoene signif-icantly suppresses cell viability, adi-pogenesis and increases apoptosis in different stages of 3T3-L1 adipocytes. However, other garlic compounds, such as DAS, DADS, DATS, deoxyalliin and allyl methyl sulphide, have no sig-nificant effect on any of the aforemen-tioned parameters at any adipocyte stage11. Generation of reactive oxygen species (ROS) and subsequent events of kinase activation (JNK and ERK), degradation of PARP-1 and translo-cation of apoptosis-inducing factor
AIF can be attributed to apoptosis in ajoene-treated 3T3-L1 adipocytes12. Similar anti-proliferative and pro-apoptotic properties of ajoene have been the key biological factors for its use with chemotherapeutic drugs, cytarabine and fludarabine, in human CD34-positive resistant myeloid leu-kaemia cells3. Diallyl trisulphide, one of the prominent components in garlic oil, inhibited the differen-tiation of preadipocytes into lipid-filled adipocytes through prolonged ERK activation, by inhibiting CCAAT/enhancer-binding protein (C/EBPα and γ) and subsequent fatty acid synthase (FAS)13. Thiacremonone, another organosulphur compound isolated from garlic, has significantly reduced differentiation of 3T3-L1 preadipocytes by down-regulating adi-pogenesis-related transcription factors
Figure 1: A list of various beneficial effects of garlic and its derivatives.
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For citation purposes: Ambati S. Garlic derivatives: role in obesity and related disorders. OA Biotechnology. 2013 Jan 14;2(1):1.
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Critical review
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eliminate undesirable cells through ROS-mediated apoptosis.
Garlic derivatives: in vivo studies
There are certain pharmaceutical formulations and prescription medi-cations that are available for weight loss in markets, but most of these are unsuccessful in reducing obesity and are often associated with some side effects. In this context, phytochemi-cals and their formulations with their ability to work—either alone or syn-ergistically in combination—have tre-mendous potential to be developed as alternative therapeutics to treat obe-sity and other associated diseases.
Various beneficial effects of garlic-derived organosulphur compounds are attributed to their anti-oxidant and anti-cancer properties. These properties of various garlic extracts and compounds have also been favoured to show lot of beneficial effects in encountering problems of
obesity. Garlic and its extracts, when supplemented with diet, have been proven to be beneficial in animals. Garlic extracts increased the growth and metabolism of interscapular brown adipose tissue (BAT) in rats through enhanced mitochondrial uncoupling protein (UCP) content. UCP is a thermogenic protein involved in dissipating energy as heat17, and garlic products increased catabo-lism of dietary cholesterols and fatty acids as observed in the studies on rodents18.
Both black garlic and its fermented version have shown promising results in protecting high fat diet-induced obesity, hyperglycaemia, liver and kidney damage in mice19. Garlic com-pounds are also reported to reduce glucocorticoids, which are primar-ily implicated in visceral and central obesity contributing to metabolic syndrome17. Furthermore, cysteine compounds of garlic decrease FAS expression, an enzyme that plays
an important role in lipid synthesis, in liver cells20. In mice, diet supple-mented with garlic has been reported to reduce the concentration of plasma triglycerides, free fatty acids and total cholesterol. In addition, up-regulation of uncoupled proteins for fat oxida-tion along with a reduction of tissue mass was noticed in epididymal adi-pose depots, indicating the benefi-cial effects of garlic supplementation in improving metabolic profile and reducing adipose tissue mass21.
Garlic derivatives and metabolic syndromeMetabolic syndrome is characterized by a combination of deteriorating health conditions such as increased blood pressure, high blood sugar level, accumulation of body fat (obesity) cul-minating in increased risk of cardiac diseases and diabetes. Anti-oxidant properties of garlic and its compounds can help address these issues. Zinc complexes with garlic components serve as insulin-mimetic22, a new ther-apeutic approach to treat diabetes, leptin resistance and to suppress pro-gression of obesity in rodent models23.
Garlic compounds and bone healthThere is an inverse relationship that prevails between adipocytes and bone-forming osteoblasts in the bone marrow2, as both adipocytes and osteoblasts are derived from a common precursor cell, the mes-enchymal stem cell. Thus, there is a positive correlation between obesity and osteoporosis and incidence of osteoporosis with the progression of obesity, at least in post-menopausal women. Stimulation of adipogen-esis at the expense of osteogenesis can lead to the accumulation of adi-pocytes in bone marrow, resulting in weaker bones. Osteoporosis and obesity have become major health concerns, as a large amount of bone mass is lost during initial years fol-lowing the onset of menopause. On
(a) Lipid-soluble garlic compounds
S
diallyl sulphide
diallyl disulphide
diallyl trisulphide
(1E)-1-(Allyl disulphanyl)-3-(allyl sulphinyl)-1-propene
allyl methyl sulphide
S
S
O
SS
S SS
S
S
S
SH
O
HS
thiacremonone
2-vinyl-4H-1,2-dithiin
S
SS
S-allylcysteine
S-allylmercaptocysteine
O
O
OH
OH
NH2
NH2
(b) Water-soluble garlic compounds
S
Figure 2: The chemical structures of some lipid-soluble (a) and water-soluble (b) organosulphur compounds of garlic.
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For citation purposes: Ambati S. Garlic derivatives: role in obesity and related disorders. OA Biotechnology. 2013 Jan 14;2(1):1.
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Critical review
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activate BAT, thereby initiating thermo-genesis30. As it is well known, obesity is a condition of energy imbalance with higher energy intake than expenditure. Activation of thermogenesis by BAT can be a source of increased expenditure, thereby restoring energy balance. Garlic derivatives may provide an opportunity to be explored in this direction.
Another important purpose of using garlic compounds is to inhibit adipogenesis by either reducing lipid accumulation or inducing adipocyte apoptosis. Although not all individual garlic compounds are as effective, some studies have suggested that aged garlic extracts or combining multiple garlic compounds can enhance their potential by synergism8. In addition to the anti-adipogenic effect of gar-lic compounds, their impact on bone health is also an important area of research to explore. Garlic derivatives have the ability to lower bone resorp-tion25, which is an important phase of bone loss in osteoporosis.
ConclusionNatural products are increasingly being considered for therapeutic pur-poses owing to their safety and lesser side effects compared with their phar-maceutically-formulated counterparts. Obesity and its related disorders are mostly diet-induced, and formulations based on phytonutrients such as garlic will be a better choice in treating these conditions. Improved processing tech-nologies and combinatorial use can make garlic derivatives much more effective tools in the prevention and treatment of these disorders.
References1. Flegal KM, Carroll MD, Kit BK, OgdenCL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012 Feb;307(5):491–7. 2. Rayalam S, Della-Fera MA, Baile CA.Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis. Mol Nutr Food Res. 2011 Aug;55(8):1177–85.
result of some complications asso-ciated with its excessive consump-tion. Burning sensation, diarrhoea and some allergic reactions have been cited as examples of side effects linked to excessive garlic consump-tion8,28. However, most of these toxic effects of garlic derivatives can be eliminated by improved and sophisti-cated processing methods. The safety limits for each garlic compound, as tested in animal models, vary, and usually, water-soluble SAC is less toxic than oil-soluble derivatives29. In addition, these differences in safety limits of garlic derivatives are a con-tributing factor to their biological and therapeutic potential8.
PerspectivesAlthough several garlic-derived organo-sulphur compounds have shown prom-ising results in cancer research in both in vitro and in vivo models, many of these compounds have not yet been explored for their potential to be used as therapeutics to treat obesity. There are many compounding factors that can affect the outcome of testing in different models. In animal models, absorption, gut microflora, metabolism, bioavail-ability and gut physiology are the key determining factors. Phytochemicals have a tendency to show more potent effects when used in combination than alone. Similar modes of increase in potency by synergism can be expected from garlic compounds when used in combinations8. The key to harvest-ing potent products from garlic is the method of extraction and purification. One of the interesting roles of garlic is to enhance thermogenesis in BAT and some other metabolically active organs such as liver. As reported in some stud-ies, garlic compounds have the abil-ity to enhance the expression levels of thermogenic proteins such as UCP1. Thermogenesis induced by UCP1 is a process of non-shivering heat genera-tion by combusting excess lipids and glucose that are accumulated in the body. Feeding some of the dietary com-ponents low in protein content can
the other hand, the net gain in bone formation is determined by a balance between mineralization and resorp-tion. Several dietary constituents and herbal products including onion and garlic show promising effects on bone health by inhibiting bone resorption24. The effects of garlic and its derivatives have been shown to play a positive role in reducing bone resorption in ovariectomized animal models25 through partial recovery of the serum oestrogen in hypogonadal rats by reducing inflammatory cyto-kines and oxidative stress26.
Garlic derivatives counteract endocrine disruptorsEndocrine disruptors are chemicals, either natural or man-made, that inter-fere with endocrine system and result in some adverse health conditions such as lowered fertility, endometrio-sis, obesity and some types of cancer. Tributyltin (TBT) is widely considered as an endocrine-disrupting chemi-cal and a potential obesity inducer. TBT makes its way into human beings through contaminated sea food and is implicated in oxidative damage both in in vivo and in vitro research mod-els. Pre-treatment with garlic oil has shown its ability as a scavenger in pre-venting TBT-induced oxidative dam-age by inhibiting ROS production and malondialdehyde content; in addition, it offers protection against DNA dam-age, nuclei and mitochondrial damage in thymocytes in mice27.
Garlic compounds: toxicityThe evaluation of product toxicity is of paramount importance before a product can be considered for thera-peutic use. Although garlic has been traditionally used in cooking for its flavour and aroma for several centu-ries without any health concerns, it is necessary to consider all toxicity issues before using it for therapeutic purposes. Some reports have even suggested using garlic derivatives in moderation, using it as a complemen-tary rather than a therapeutic8, as a
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For citation purposes: Ambati S. Garlic derivatives: role in obesity and related disorders. OA Biotechnology. 2013 Jan 14;2(1):1.
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syndrome. Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):237–52. 23. Adachi Y, Yoshida J, Kodera Y, Kato A,Yoshikawa Y, Kojima Y, et al. A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes. J Biol Inorg Chem Publ Soc Biol Inorg Chem. 2004 Oct;9(7):885–93. 24. Putnam SE, Scutt AM, Bicknell K,Priestley CM, Williamson EM. Natural products as alternative treatments for metabolic bone disorders and for main-tenance of bone health. Phytother Res. 2007 Feb;21(2):99–112.25. Mukherjee M, Das AS, Mitra S, Mitra C. Prevention of bone loss by oil extract of garlic (Allium sativum Linn.) in an ovari-ectomized rat model of osteoporosis. Phytother Res. 2004 May;18(5):389–94. 26. Mukherjee M, Das AS, Das D,Mukherjee S, Mitra S, Mitra C. Role of peritoneal macrophages and lympho-cytes in the development of hypogonadal osteoporosis in an ovariectomized rat model: possible phytoestrogenic effi-cacy of oil extract of garlic to preserve skeletal health. Phytother Res. 2007 Nov;21(11):1045–54.27. Liu HG, Xu LH. Garlic oil preventstributyltin-induced oxidative damage in vivo and in vitro. J Food Prot. 2007 Mar;70(3):716–21. 28. Mader FH. Treatment of hyperlipidae-mia with garlic-powder tablets. Evidence from the German Association of General Practitioners’ multicentric placebo-con-trolled double-blind study. Arzneimittel-Forschung. 1990 Oct;40(10):1111–6. 29. Imada O, editor. Toxicity aspects ofgarlic. First world congress on the health significance of garlic and garlic constitu-ents; 1990; Washington, DC.30. Cannon B, Nedergaard J. Brownadipose tissue: function and physi-ological significance. Physiol Rev. 2004 Jan;84(1):277–359.
13. Lii CK, Huang CY, Chen HW, Chow MY,Lin YR, Huang CS, et al. Diallyl trisulfide suppresses the adipogenesis of 3T3-L1 preadipocytes through ERK activation. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2012 Mar;50(3–4):478–84. 14. Lee JH, Kim KA, Kwon KB, Kim EK, Lee YR, Song MY, et al. Diallyl disulfide accel-erates adipogenesis in 3T3-L1 cells. Int J Mol Med. 2007 Jul;20(1):59–64. 15. Xiao D, Pinto JT, Gundersen GG,Weinstein IB. Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells. Mol Cancer Ther. 2005 Sep;4(9):1388–98.16. Tsai CW, Liu KL, Lin CY, Chen HW, LiiCK. Structure and function relationship study of allium organosulfur compounds on upregulating the pi class of gluta-thione S-transferase expression. J Agric Food Chem. 2011 Apr;59(7):3398–405. 17. Oi Y, Kawada T, Shishido C, WadaK, Kominato Y, Nishimura S, et al. Allyl-containing sulfides in garlic increase uncoupling protein content in brown adipose tissue, and noradrenaline and adrenaline secretion in rats. J Nutr. 1999 Feb;129(2):336–42. 18. Shoetan A, Augusti KT, Joseph PK.Hypolipidemic effects of garlic oil in rats fed ethanol and a high lipid diet. Experientia. 1984 Mar;40(3):261–3. 19. Jung YM, Lee SH, Lee DS, You MJ,Chung IK, Cheon WH, et al. Fermented garlic protects diabetic, obese mice when fed a high-fat diet by anti-oxidant effects. Nutr Res. 2011 May;31(5):387–96. 20. Liu L, Yeh YY. Water-soluble organo-sulfur compounds of garlic inhibit fatty acid and triglyceride syntheses in cul-tured rat hepatocytes. Lipids. 2001 Apr;36(4):395–400. 21. Yangha Kim M-SL, Kim L-S, LeeH-S. Garlic decreases body weight via decrease of serum lipid and increase of uncoupling proteins mRNA expression. FASEB J. 2007;21:1.22. Banos G, Perez-Torres I, El Hafidi M. Medicinal agents in the metabolic
3. Hassan HT. Ajoene (natural garliccompound): a new anti-leukaemia agent for AML therapy. Leukemia Res. 2004 Jul;28(7):667–71. 4. Kim EJ, Lee DH, Kim HJ, Lee SJ, BanJO, Cho MC, et al. Thiacremonone, a sulfur compound isolated from garlic, attenuates lipid accumulation partially mediated via AMPK activation in 3T3-L1 adipocytes. J Nutr Biochem. 2012 Dec;23(12):1552–8. 5. Keophiphath M, Priem F, Jacquemond-Collet I, Clement K, Lacasa D. 1,2-Vinyldithiin from garlic inhibits differentiation and inflammation of human preadipocytes. J Nutr. 2009 Nov;139(11):2055–60. 6. Ban JO, Lee DH, Kim EJ, Kang JW, KimMS, Cho MC, et al. Antiobesity effects of a sulfur compound thiacremonone mediated via down-regulation of serum triglyceride and glucose levels and lipid accumulation in the liver of db/db mice. Phytother Res. 2012 Sep;26(9):1265–71. 7. Butt MS, Sultan MT, Iqbal J. Garlic:nature’s protection against physiologi-cal threats. Crit Rev Food Sci Nutr. 2009 Jun;49(6):538–51.8. Amagase H. Clarifying the real bioac-tive constituents of garlic. J Nutr. 2006 Mar;136(3 Suppl):716S–25S. 9. Park JH, Park YK, Park E. Antioxidativeand anti-genotoxic effects of garlic (Allium sativum L.) prepared by different processing methods. Plant Foods Hum Nutr. 2009 Dec;64(4):244–9. 10. Iciek M, Kwiecien I, Wlodek L. Biological properties of garlic and garlic-derived organosulfur compounds. Environ Mol Mutagen. 2009 Apr;50(3):247–65. 11. Ambati S, Yang JY, Rayalam S, ParkHJ, Della-Fera MA, Baile CA. Ajoene exerts potent effects in 3T3-L1 adipo-cytes by inhibiting adipogenesis and inducing apoptosis. Phytother Res. 2009 Apr;23(4):513–8. 12. Yang JY, Della-Fera MA, Nelson-Dooley C, Baile CA. Molecular mechanisms of apoptosis induced by ajoene in 3T3-L1 adipocytes. Obesity (Silver Spring). 2006 Mar;14(3):388–97.
