New Mechanisms and The Anti-Inflammatory Role of Curcumin in Obesity and Obesity-Related Metabolic Diseases

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Eur J Nutr (2011) 50:151–161

DOI 10.1007/s00394-011-0188-1

REVIEW

New mechanisms and the anti-inflammatory role of curcumin


in obesity and obesity-related metabolic diseases
Adeeb Shehzad • Taewook Ha • Fazli Subhan •

Young Sup Lee

Received: 14 October 2010 / Accepted: 15 February 2011 / Published online: 27 March 2011
Ó Springer-Verlag 2011

Abstract a major risk to the health system. Curcumin interacts with


Purpose A metabolic abnormality such as obesity is a specific proteins in adipocytes, pancreatic cells, hepatic
major obstacle in the maintenance of the human health stellate cells, macrophages, and muscle cells, where it
system and causes various chronic diseases including type suppresses several cellular proteins such as transcription
2 diabetes, hypertension, cardiovascular diseases, as well factor NF-kB, STAT-3, Wnt/b-catenin and activates
as various cancers. This study was designed to summarize PPAR-c, Nrf2 cell signaling pathway. In addition, curcu-
the recent scientific knowledge regarding the anti-obesity min downregulates the inflammatory cytokines, resistin
role of curcumin (diferuloylmethane), which is isolated and leptin, and upregulates adiponectin as well as other
from the herb curcuma longa, known to possess anti- associated proteins. The interactions of curcumin with
inflammatory activities. However, little is known about its several signal transduction pathways reverse insulin resis-
exact underlying molecular mechanisms in the treatment of tance, hyperglycemia, hyperlipidemia, and other inflam-
obesity and metabolic diseases. Furthermore, cell cultures, matory symptoms associated with obesity and metabolic
animal models of obesity, and few human clinical and diseases.
epidemiological studies have added the promise for future Conclusion The modulation of several cellular transduc-
therapeutic interventions of this dietary compound. tion pathways by curcumin has recently been extended to
Methods An electronic search was performed using Sci- elucidate the molecular basis for obesity and obesity-rela-
ence finder, Medline, Scopus, Google scholar and collected ted metabolic diseases. These findings might enable novel
English language articles from 2000 to 2010, relating to the phytochemical treatment strategies as well as curcumin
role of curcumin in obesity and metabolic diseases. translation to the clinical practice for the treatment and
Results Obesity has been classified as a growing epi- prevention of obesity-related chronic diseases. Further-
demic and its associated metabolic disorders are considered more, the relatively low cost of curcumin, safety and pro-
ven efficacy make it advisable to include curcumin as part
of healthy diet.
A. Shehzad  T. Ha  Y. S. Lee (&)
School of Life Sciences, College of Natural Sciences,
Keywords Curcumin  Obesity  Inflammation 
Kyungpook National University, 1370 Sangeok-dong,
Buk-ku, Daegu 702-701, Korea Adipocytes  Adiponectin
e-mail: yselee@knu.ac.kr
A. Shehzad
e-mail: Adeeb.shehzad@gmail.com Introduction
T. Ha
e-mail: koreahatu@nate.com The worldwide incidence of obesity has been rapidly
increasing in the last two decades. According to a W.H.O
F. Subhan
report, obesity has been classified as a growing epidemic,
Department of Biology, College of Natural Sciences,
Kyungpook National University, Daegu 702-701, Korea and if immediate action was not taken, millions will suffer
e-mail: fazli_biotech@yahoo.com from an array of serious weight-related disorders. Obesity

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counts a major health problem and common chronic dis- It interacts indirectly with several transcription factors,
ease, affecting more than 1 in 4 of all Americans, including including nuclear factor-kappa B (NF-kB), activator protein
children, and its incidence has been steadily increasing in 1 (AP-1), b-catenin, signal transducer and activator of
the last two decades. In health surveys conducted in the transcription (STAT) proteins, and peroxisome prolifera-
United States in 2005, 24.2% of men and 23.5% of women tor–activated receptor c (PPARc) [11]. Curcumin modulates
or over one-fifth of the respondents were classified as obese multiple molecular targets and has potent anti-inflammatory
[1]. Similarly, in the United Kingdom, a survey conducted activities, which might contribute to its therapeutic role in
in 2007 found that 21.9% of men and 24.4% of women obesity and obesity-related metabolic diseases.
were obese [2]. According to German government statistics After summarizing the background epidemiological
report, two-thirds of all German men between the ages of observations, this review details the evidence behind these
18 and 80 are overweight; almost half of all women have various, often overlapping, mechanisms and briefly men-
weight problems, and more than 1 million of their youth tions curcumin’s anti-inflammatory role in the prevention
show symptoms of eating disorders [http://EzineArticles. and treatment of obesity and obesity-related metabolic
com/?expert=Vreel_Mistee]. Several studies have shown diseases. It is hoped that this study will add new insights
that obesity is associated with an increase in mortality into the molecular pathways that are mediated by curcumin
rates. Those persons who suffer from obesity have a in obesity and may hold promise for future therapeutic
10–50% increased risk of death from natural causes com- intervention.
pared with those of normal healthy weight individuals. This
increased risk of death is due to the obesity-induced car-
diovascular diseases, which accounts for about 112,000 Inflammation and obesity-related metabolic diseases
deaths per year in the United States population, compared
with healthy weight individuals [http://www.cdc.gov/ Inflammation is a major component of obesity that is
obesity/index.html]. associated with insulin resistance (Fig. 1). Pharmacological
Obesity arises when there is an imbalance between or genetic inhibition of pathways that underlie inflamma-
energy intake, principally stored as triglycerides (food tory responses has been found to protect experimental
consumption), and energy expenditure (basal metabolic animals and human subjects from diet-induced insulin
rate and biochemical processes). The excess energy is resistance [12]. The subclinical or chronic inflammation
primarily stored in adipose tissue in the form of triglycer- has been recognized, as being involved in the development
ides. When adipose tissue function is compromised during of obesity, type 2 diabetes, and obesity-related athero-
obesity, the excessive fat accumulation in adipose tissue, sclerosis [13]. An important initiator of the inflammatory
liver, and other organs predisposes the individual to the response to obesity is adipose tissue, which is involved in
development of metabolic changes that increase overall energy regulation and homeostasis. It is now understood
morbidity risks [3, 4]. Obesity is a complex trait influenced that adipose tissue is not simply a storage depot for excess
by diet, developmental stage, age, physical activity, and calories but that it also actively secretes fatty acids and a
genes [5]. Obesity is also a significant risk factor for major variety of polypeptides, which can function in an endocrine
diseases including Type 2 diabetes, coronary heart disease, or paracrine fashion as well as sensitive to insulin. Thus,
hypertension, and certain forms of cancer including gas- the mixture of adipokines secreted by adipose tissue in a
trointestinal, ovary, breast, uterus, cervical, pancreatic, given path physiological state is commonly associated with
hepatic, kidney, multiple myeloma, and lymphoma [6–8]. obesity. The adipose tissue consists of a variety of cell
In addition, international Agency for Research on Cancer types, including adipocytes, immune cells (macrophages
(IARC) used obesity prevalence data from Europe and and lymphocytes), pre-adipocytes, and endothelial cells.
relative risks from a meta-analysis of published studies, Adipocytes uniquely secrete adipokines, such as leptin,
had shown that obesity was a cause of 11% of colon cancer, adiponectin, resistin as well as inflammatory cytokines
9% of postmenopausal breast cancer, 39% of endometrial such as TNF and interleukins 1, 6 (IL-1, IL-6) [14–16].
cancer, 25% of kidney cancer, and 37% of esophageal These factors are critically involved in obesity-induced
cancer cases [9]. insulin resistance and chronic inflammation. Hajri et al.
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6- proposed that TNF-a and IL-6 expression and secretion
heptadiene-3,5dione], the active constituent of turmeric, has increased significantly in the adipose tissue of obese sub-
been used as a treatment for a wide variety of inflammatory jects and were negatively associated with those of adipo-
ailments, including obesity and other metabolic diseases. nectin. In 3T3-L1 and human adipocyte cultures, insulin
Curcumin interacts directly with cyclooxygenase-2 (COX- strongly enhanced adiponectin expression (twofold) and
2), DNA polymerase, lipoxygenase (LOX), glycogen syn- secretion (threefold). It is believed that insulin upregulates
thase kinase-3b (GSK-3b), and cytokines (TNF-a) [10]. adiponectin expression and that TNF-a opposes the

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Eur J Nutr (2011) 50:151–161 153

into the circulation and impair insulin sensitivity in distal


tissues through endocrine effects [24, 25].
NF-kB is a transcription factor that widely acts as a
regulator of genes that control cell proliferation and cell
survival, as well as promote insulin resistance through
inflammation and cytokine production. In adipocytes,
inflammatory signals including TNF-a lead to an activation
of IKK, which then phosphorylates the inhibitor of NF-kB
(IkB). In the resting state, IkB forms a complex with NF-
kB, restricting NF-kB to a cytoplasmic location. After
phosphorylation, IkB dissociates from NF-kB and under-
goes degradation. The released NF-kB translocates to the
nucleus, where it binds to its specific DNA response ele-
ments, leading to transactivation of inflammatory pathway
genes. Several studies have shown that lipid accumulation
in the liver leads to hepatic inflammation through NF-kB
activation and downstream cytokine production, which
leads to insulin resistance hepatically as well as systemi-
cally [26, 27]. Several studies have also demonstrated that
Fig. 1 A model illustrating the multiple inflammatory molecular Toll-like pattern recognition receptors play an important
targets and cell signaling complexes in obesity and insulin resistance.
Cell signaling intermediates indicated in circles are downregulated,
roles in mediating pro-inflammatory effects of saturated
without circles are upregulated, and cross lines indicate inhibition fatty acids, particularly Toll-like receptor 4 (TLR4), which
induces insulin resistance through activation of NF-kB.
TLR4 expression is increased in obesity, and when this
receptor is deleted, saturated fatty acid induced inflam-
stimulatory effects of insulin [17]. Studies have demon- mation, which is impaired in adipocytes and skeletal
strated the elevated levels of adipose IL-6 and TNF-a muscle cells [28, 29]. Similarly, the other major intracel-
mRNA in obese subjects and a decrease was observed in lular pro-inflammatory pathway involved in obesity is
IL-6 and TNF-a with weight loss [18]. High TNF secretion c-Jun N-terminal protein kinase 1/AP-1 (JNK1/AP1) sys-
from human adipose tissue was associated with decreased tem [30]. In this pathway, external inflammatory signals
[3H] glucose incorporation into lipids [19]. TNF phos- lead to the phosphorylation and activation of JNK, which
phorylates S6K1 (p70S6K) known to impair insulin resis- then phosphorylates the N terminus of c-Jun on target
tance through serine phosphorylation of insulin receptor genes. This induces an exchange of c-Jun dimers for c-Jun/
substrate (IRS-1), which then inhibits the tyrosine kinase c-Fos heterodimers, transactivating a set of inflammatory
activity of the insulin receptor in adipocytes and hepato- pathway genes, which substantially overlap with the set of
cytes [20]. In addition, dephosphorylation of serine in genes transactivated by NF-kB [31, 32].
IRS-1 was also associated with the overexpression of the PPARs belong to the superfamily of nuclear hormone
dual-specificity phosphatase MKP-4/DUSP-9 that found to receptors, which antagonize the activities of NF-kB and
protect against stress-induced insulin resistance [21]. TNF have potential role in inflammatory conditions such as
also induces protein tyrosine phosphatase (PTP)-1B, which obesity. Among PPARs, PPAR-c is a known molecular
acts as a negative regulator of TNF signaling, and mice target in the treatment of type 2 diabetes, for all insulin-
lacking PTP-1B are protected from TNF-induced insulin sensitizing drugs [33]. It has been observed that insulin
resistance [22]. Numerous studies have shown that a resistance may be linked with downregulation of PPAR-c
blockade of TNF receptor type 1–mediated TNF-a signal- by TNF. In addition, TNF induced NF-kB that blocks
ing protected Wistar rats from diet-induced obesity and the PPAR-c binding to DNA, by forming complex with
insulin resistance [23]. Moreover, circulating concentra- PPAR-c and its AF-1-specific co-activator PGC-2 [34].
tions of inflammatory cytokines are considered to be the A lot of compelling evidence has suggested that
most important factor in causing and maintaining insulin increased infiltration of macrophages in white adipose tis-
resistance, although the normal mode of cytokine-mediated sue (WAT) is also an important source of inflammation in
insulin resistance involves local paracrine effects, elevated obesity. Histological studies indicated that these macro-
levels of the inflammatory cytokines such as TNF-a, IL-6, phages are primarily localized to the intramuscular adipose
and IL-1b have been reported in obesity, insulin-resistant depots, which accumulate within skeletal muscle in obes-
states, raising the possibility that tissue cytokines can leak ity. Many inflammatory and macrophage-specific genes are

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154 Eur J Nutr (2011) 50:151–161

considerably upregulated in WAT in mouse models of Table 1 Molecular targets of curcumin in obesity and metabolic
genetic and high-fat diet-induced obesity (DIO). The diseases
upregulation is progressively increased in WAT of mice Transcription factors References
with DIO by macrophage-related inflammatory activities Activator protein-1 57
and contributes to the pathogenesis of obesity-induced b-catenin 40
insulin resistance [35]. In summary, inflammation repre- GATA binding protein 4 62
sents a major role in the progression of obesity toward Nuclear factor-kappa B 39
insulin resistance. Nuclear factor E2–related factor 45
Peroxisome proliferator–activated receptor c 50
Signal transducers and activator of transcription 51
Curcumin molecular targets in obesity and metabolic Sterol regulatory element binding protein-2 53
diseases Adipokines
Tumor necrosis factor a 51
In the last two decades, a huge amount of research has been Interleukins 38
published on curcumin, which revealed that it modulates Leptin 47
many regulatory proteins, including those of transcription Adiponectin 49
factors, enzymes, cytokines, and growth factors (Table 1). Resistin 36
Studies have shown that curcumin inhibits a number of Monocyte chemotactic proteins 39
signaling pathways and molecular targets involved in Enzymes
inflammation and obesity-related metabolic diseases [36]. Arylamine N-acetyltransferases-1 67
Curcumin can inhibit the IKK signaling complex that is Cyclooxygenase-2 38
responsible for the phosphorylation of IkB, thereby block- Inducible nitric oxide synthase 65
ing improper activation of NF-kB induced by various Lipoxygenase 10
inflammatory agents [37]. Anti-obesity effects of curcumin Matrix metalloproteinases 54
are also linked with the inhibition of inflammatory and NADPH:quinine oxidoreductase 58
angiogenic biomarkers such as COX-2 and vascular endo- Phospholipase D 10
thelial growth factor (VEGF). Curcumin downregulates the Haem oxygenase-1 54
expression of various pro-inflammatory cytokines including Growth factors
TNF-a, VEGF, interleukins 1, 2, 6, 8, 12 (IL-1, IL-2, IL-6, Connective tissue growth factor 54

IL-8, IL-12) by inactivation of the NF-kB. Studies have Epidermal growth factor 46
Hepatocyte growth factor 53
shown that curcumin treatment reduced the tumor-induced
Platelet-derived growth factor 70
overexpression of COX-2 and serum VEGF in HepG2
Transforming growth factor-b 54
groups significantly (p \ 0.001), indicating that curcumin
Vascular endothelial growth factor 38
has potential role in angiogenesis [38]. In addition, curcu-
Kinases
min has been shown to downregulate the expression of
AMP-activated protein kinase 50
various NF-kB-regulated proinflammatory adipocytokines
Focal adhesion kinase 54
including chemokines (such as monocyte chemotactic
Glycerol-3-phosphate acyltransferase 1 67
protein 1, 4 (MCP-1, MCP-4), and eotaxin) [39]. Curcumin
Protein kinases 49
was reported as excellent inhibitors of b-catenin/TCF-LEF
Protein tyrosine kinase 57
and hence reduced the b-catenin/TCF signaling, which is
Receptors
closely linked to obesity. This effect is mediated through the
Insulin receptors 67
inhibition of the GSK-3b, which is responsible for the
Chemokine receptor 4 39
b-catenin phosphorylation [40]. Recent studies have shown
Epidermal growth factor receptor 46
that curcumin-induced suppression of adipogenic differen-
Histamine 2-receptor 36
tiation in 3T3-L1 cells is accompanied by activation of Wnt/
Integrin receptor 65
b-catenin signaling. During differentiation, curcumin
Low-density lipoprotein receptor 67
restored nuclear translocation of the integral Wnt signaling
Others
component beta-catenin in a dose-dependent manner. In Urokinase-type plasminogen activator 46
parallel, curcumin reduced differentiation-stimulated Triglycerides 71
expression of CK1a, GSK-3b, and Axin, components of the Plasma free fatty acids 67
destruction complex targeting b-catenin [41]. Several Iron regulatory protein 71
studies have also demonstrated the antioxidant role of cur- Antioxidant-responsive element 58
cumin in obesity. Transcription factors such as AP-1 are

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Eur J Nutr (2011) 50:151–161 155

activated in response to stress, growth factors, and inflam- apoptosis in adipocytes. Research evidence narrated that
matory cytokines. Curcumin can inhibit the stress-stimu- curcumin inhibits the differentiation of pre-adipocytes to
lated activation of AP-1 and has been shown to ameliorate adipocytes and inhibited adipokine-induced angiogenesis
oxidative stress–induced renal injury in mice [42]. Curcu- of human endothelial cell through suppression of VEGF-a.
min in the dose of 10 lM prevented the protein glycosyl- Curcumin treatment in C57/BL mice increased the fatty
ation and lipid peroxidation caused by high glucose levels acid oxidation in adipocytes and also increased the activity
in erythrocyte cell model. Curcumin inhibited oxygen free of AMP-activated protein kinase (AMPK) by phosphory-
radical production caused by high glucose concentrations in lating the a-subunit of AMPK, as well as suppressed the
a cell-free system and increased glucose utilization in expression of amino-cyclopropane carboxylic acid by
erythrocytes [43]. Numerous studies have indicated that phosphorylation [49]. Lee et al. investigated the effect of
curcumin reduces serum cholesterol concentrations by curcumin on cancer and obesity and suggested that acti-
increasing the expression of hepatic low-density lipoprotein vation of AMPK by curcumin was crucial for the inhibition
(LDL) receptors, blocks the oxidation of LDL, increased of differentiation or growth in both adipocytes and cancer
bile acid secretion and metabolic excretion of cholesterol, cells. Curcumin-stimulated AMPK resulted in the down-
represses the expression of genes involved in cholesterol regulation of PPAR-c in 3T3-L1 adipocytes and decreased
biosynthesis, and protects against liver injury and fibro- the COX-2 expression. Application of a synthetic AMPK
genesis in animal models [36]. The hypocholesterolemic activator also supported evidence that AMPK acts as an
effect of curcumin was correlated with increase in LDL- upstream signal of PPAR-c in 3T3-L1 adipocytes. It is
receptor mRNA, whereas mRNAs of the genes encoding the suggested that regulation of AMPK and its downstream
sterol biosynthetic enzymes HMG CoA reductase and far- targets such as PPAR-c, mitogen activated protein kinase
nesyl diphosphate synthase were only slightly increased in (MAPK), and COX-2 by curcumin appears to be important
human hepatoma cell line (HepG2). Although curcumin in controlling adipocytes and cancerous cells [50]. Curcu-
strongly inhibited alkaline phosphatase activity, an activa- min increased the insulin-stimulated glucose uptake in
tion of a retinoic acid response element reporter employing 3T3-L1 cells and suppressed the transcriptional secretion
alkaline phosphatase secretion was observed [44]. More- of TNF-a and IL-6 induced by palmitate in a concentration-
over, curcumin has been identified as a potent inducer of dependent manner through the inhibition of NF-kB. It is
hem oxygenase-1 (HO-1), a redox-sensitive inducible pro- concluded that curcumin reverses palmitate-induced insu-
tein via regulation of nuclear factor E2-related factor 2 lin resistance state in 3T3-L1 adipocytes through the
(Nrf2) and the antioxidant-responsive element (ARE), inhibition of NF-kB and JNK [51]. In addition, curcumin
which provides protection against various forms of stress. enhances the expression of adiponectin in adipocytes,
Curcumin stimulates HO-1 gene activity through inactiva- which inhibits NF-kB activation and negatively controls
tion of the Nrf2–Keap1 complex, leading to increased Nrf2 obesity [48]. Studies have also shown that curcumin sig-
binding to the resident HO-1 and AREs [45]. The early nificantly inhibited the cellular production of proinflam-
growth response (Egr-1) gene is a transcription factor that matory mediators such as TNF-a and nitric oxide and
modulates the activity of plasminogen activator inhibitor significantly inhibited the release of MCP-1 from 3T3-L1
type-1 that has been associated with insulin resistance and adipocytes. Curcumin dose dependently inhibited phorbol
obesity. Curcumin inhibits the expression of the plasmino- myristate acetate (PMA)-induced MCP-1 expression by
gen activator inhibitor type-1 by reducing the activity of inhibiting ERK and NF-kB transcriptional activity in U937
Egr-1 in obesity-related diseases [46]. Several studies have cells [52]. These studies suggest that curcumin can
shown that curcumin blocks the leptin signaling by reducing suppress obesity-induced inflammatory responses and
the phosphorylation levels of the leptin receptor (Ob-R) and modulate adipose tissue macrophage accumulation or
increases the induction of adiponectin, which improves activation [39].
obesity-associated inflammation [47, 48]. These finding
support the existence of direct and indirect molecular
mechanisms by which curcumin inhibits several inflam- Curcumin role in hepatic stellate cells
matory pathways that are responsible for obesity and
obesity-related metabolic diseases. Curcumin inhibited hepatic stellate cells (HSC) activation
and intervened in liver fibrogenesis associated with hy-
perleptinemia in nonalcoholic steatohepatitis (NASH)
Curcumin role in adipocytes patients. HSCs are the major effector cells during liver
fibrogenesis and could be activated by leptin. Curcumin
Several studies have shown the potential role of cur- abrogated the stimulatory effect of leptin on HSC activa-
cumin in angiogenesis, adipogenesis, differentiation, and tion in vitro by reducing the phosphorylation level of Ob-R,

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stimulating PPAR-c activity, and attenuating oxidative potent inducers of phase 2 enzyme HO-1, via regulation of
stress, which leads to the suppression of Ob-R gene nuclear factor Nrf2 and the ARE in mouse beta cells.
expression and elimination of leptin signaling [47]. In the Curcumin stimulates HO-1 gene activity, which is corre-
same cells, Woo HM and his coworkers have shown that lated with the increase in the expression of glutamyl cys-
curcumin inhibited LDL-induced HSC activation in vitro teine ligase (GCL) needed for glutathione (GSH)
by repressing gene expression of the transcription factor biosynthesis and NADPH2:quinone reductase, which det-
sterol regulatory element binding protein-2 (SREBP-2) by oxifies quinines [45, 58]. In addition, curcumin protected
activating PPAR-c, thus reducing the specificity protein-1 beta cells from oxidative stress through increased GSH islet
(SP-1) activity, which leads to the repression of ldlr content and basal insulin secretions. It has also been
expression. Activation of PPAR-c has been linked to the observed that curcumin protected islets from cytokine-
reduction in the level of intracellular cholesterol in HSCs induced islet death in vitro by scavenging ROS and
and to the attenuation of the stimulatory effects of LDL on normalized cytokine-induced NF-kB translocation by
HSCs activation [53]. In vitro studies have also shown that inhibiting phosphorylation of the inhibitor of kappa B alpha
activation of PPAR-c is required for curcumin to induce (IkBa). In vivo, this group observed that curcumin also
apoptosis and to inhibit the expression of extracellular prevented the progression of diabetes induced by strepto-
matrix genes in HSC. Curcumin suppressed the expression zotocin (STZ), which is associated with the suppression of
of gene products regulated by PPAR-c including a1 col- pro-inflammatory cytokine (TNF-a and IL-1b). Inflamma-
lagen, a-smooth muscle actin (a-SMA), connective tissue tory cytokine concentrations in the serum and pancreas
growth factor (CTGF), and receptors for TGF-b, platelet- were raised in STZ-treated animals, but not in animals
derived growth factor beta (PDGF-b), and epidermal pretreated with curcumin before STZ [59]. Currently,
growth factor (EGF) [54]. Recently, it has been shown that Karthikesan et al. have shown that combined treatment of
curcumin protected HSCs against leptin-induced activation tetrahydrocurcumin and chlorogenic acid exerts potential
by accumulating intracellular lipids. Curcumin eliminated antihyperglycemic effect on streptozotocin/nicotinamide-
the stimulatory effects of leptin on HSCs activation and induced diabetic rats [60].
increased AMPK activity, leading to induced expression of
genes relevant to lipid accumulation and elevated levels of
intracellular lipids [55]. The same research group also Curcumin role in obesity-related diseases
reported that curcumin prevents leptin raising glucose
levels in hepatic stellate cells by blocking translocation of Curcumin effects in animals
glucose transporter-4 (GLUT4) and increasing glucokinase.
Curcumin prevented leptin from elevating levels of intra- Until recently, the relation between obesity and coronary
cellular glucose in rat HSCs and immortalized human heart disease was viewed as indirect, that is, through
hepatocytes by inhibiting the membrane translocation of covariates related to both obesity and coronary heart dis-
GLUT4 and inducing the conversion of glucose to glucose- ease risk, including hypertension, dyslipidemia, particu-
6-phosphate (G-6-P), leading to the inhibition of HSC larly reductions in high-density lipoprotein (HDL)
activation [56]. These observations suggest a novel insight cholesterol, and impaired glucose tolerance or type 2 dia-
into mechanism of curcumin that mediates its effects on betes, although most of the comorbidities relating obesity
HSCs through direct and indirect activation of PPAR-c as to coronary artery diseases increase as body mass index
well as by inhibiting leptin-induced HSCs activation. (BMI) and related to body fat distribution. Pongchaidecha
et al. and his coworkers have shown that curcumin ame-
liorated cardiac sympathovagal disturbance in high-fat-
Curcumin role in pancreatic cells induced obese rats. In one study, male Wistar rats were fed
with curcumin 30, 60, and 90 mg/kg body weight every
Activated pancreatic stellate cells (PSCs) play a pivotal role day for 12 weeks. The researcher observed an elevated
in the pathogenesis of pancreatic fibrosis and inflammation. plasma FFA level in high-fat-induced obese rats, which is
Curcumin decreased the pancreatic beta cell volume, which associated with an increased low-frequency/high-frequency
could be associated with hypoglycemic/antidiabetic effects (LF/HF) ratio, an expression of sympathovagal distur-
of this agent. Curcumin inhibited PDGF-induced prolifer- bance. Curcumin supplementation ameliorated cardiac
ation, a-SMA gene expression, interleukin-1b- and TNF-a- autonomic imbalance in high-fat-fed rats, by lowering the
induced MCP-1 production, type I collagen production, and FFA plasma concentration [61]. In addition, Morimoto
activation of AP-1 in activated PSCs. Curcumin also et al. found that curcumin inhibited the hypertrophy-
inhibited PDGF-BB-induced cyclin D1 expression and induced acetylating and DNA-binding abilities of GATA
activation of ERK [57]. Curcumin has been reported as binding protein 4 (GATA4), a hypertrophy-responsive

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Eur J Nutr (2011) 50:151–161 157

transcription factor, in rat cardiomyocytes. Curcumin also treatment significantly attenuated cognitive deficit, cholin-
disrupted the p300/GATA4 complex and repressed p300- ergic dysfunction, oxidative stress, and inflammation in
induced hypertrophic responses in these cells. In addition, diabetic rats [68].
the effects of curcumin were examined in vivo in 2 dif-
ferent heart failure models, hypertensive heart disease in Curcumin effects in humans
salt-sensitive Dahl rats and in surgically induced myocar-
dial infarction rats. In both models, curcumin prevented the Numerous studies have been carried out in human subjects
deterioration of systolic function and heart failure-induced with curcumin to examine its effect on obesity-related
increase in myocardial wall thickness and diameter [62]. parameters. Cardiovascular complications are common in
LDL oxidation plays an important role in the development patients with obesity and to some extent are related with
of atherosclerosis (a disease characterized by oxidative increased FFA level. Curcumin has been observed to lower
damage) and inhibition of LDL oxidation can reduce the blood sugar levels in diabetic patients. Curcumin admin-
risk of atherosclerosis. Curcumin effects were evaluated istration also reduced the serum levels of cholesterol and
based on the development of experimental atherosclerosis lipid peroxides in 10 healthy human volunteers receiving
in rabbits and its interaction with other plasmatic antioxi- 500 mg of curcumin daily for 7 days. A significant
dants. Rabbits were fed an atherogenic diet for 30 days, decrease in the level of serum lipid peroxides (33%), an
and histological results for the fatty streak lesions revealed increase in high-density lipoproteins (HDL) cholesterol
damage in the thoracic and abdominal aorta that was sig- (29%), and a decrease in total serum cholesterol (12%)
nificantly lower in the curcumin fed group than in the were noted. Ramirez Bosca et al. found that administration
control group after 30 days [63]. of 10 mg of curcumin per day for 30 days to 8 human
Diabetes is also the most common cause of kidney fail- subjects increased HDL cholesterol and decreased LDL
ure, and nearly 180,000 people in the USA are living with cholesterol. The same research group also investigated the
kidney failure as a result of diabetes [64]. Diabetic effect of curcumin in human subjects with atherosclerosis,
nephropathy is characterized by increased production of in which 10 mg curcumin was administered twice a day for
extracellular matrix (ECM) proteins including fibronectin 15 days to 16 men and 14 women. Curcumin significantly
and extradomain B containing fibronectin that are regulated lowered the levels of plasma fibrinogen in both men and
by TGF-b1, NF-kB and p300 in the kidneys. Curcumin women [69, 70]. Idrus et al. conducted an interventional,
treatment inhibited p300, suppressed the activation of NF- randomized, double-blind, controlled trial to investigate the
kB, and decreased TGF-b, vasoactive factors (endothelial effects of curcumin administration at escalating doses (low
nitric oxide synthase and endothelin-1), and ECM [65]. A dose 3 times 15 mg/day, moderate dose 3 times 30 mg/
decrease in the blood glucose level in diabetic models has day, and high dose 3 times 60 mg/day) on total cholesterol
been reported in obesity studies regarding the curcumin. level, LDL cholesterol level, HDL cholesterol level, and
Diabetic albino rats were fed with curcumin (0.08 g/kg triglyceride level in 75 acute coronary syndrome (ACS)
body weight) and a decrease was observed in blood sugar patients. Based on 63 patient’s results, it is concluded that
levels when compared with the control group [66]. In the administration of low-dose curcumin showed a trend of
another study, Seo et al. investigated the effect of curcumin reduction in total cholesterol level and LDL cholesterol
supplementation on blood glucose, plasma insulin, and level in ACS patients [71]. However, Baum et al. and his
glucose homeostasis-related enzyme activities in diabetic coworkers reported that curcumin consumption does not
db/db mice, which were fed with curcumin (0.02%, wt/wt) appear to have a significant effect on the serum lipid profile
for 6 weeks. In db/db mice, curcumin significantly lowered in 6 months’ human study, contrary to the previous
the hepatic activities of fatty acid synthase, beta-oxidation, reported studies. A 6-month placebo, randomized, double-
3-hydroxy-3-methylglutaryl coenzyme reductase, and ratio blinded trial investigated the effects of consuming curcu-
of acyl-CoA to cholesterol acyltransferase. Curcumin low- min (4 and 1 g/day) on the serum lipid profile in both elder
ered plasma FFA, cholesterol, triglyceride concentrations genders (n = 36). Plasma curcumin and its metabolites
and increased the hepatic glycogen and skeletal muscle were measured at 1 month, and the serum lipid profile was
lipoprotein lipase in db/db mice [67]. Epidemiological data measured at baseline, 1, and 6 months. The plasma cur-
indicated that diabetes is a potential predisposing factor for cumin concentration reached a mean of 490 nmol/L but did
neuropsychiatric deficits such as stroke, cerebrovascular not significantly affect triacylglycerols or total, LDL, and
diseases, diabetic encephalopathy, depression, and anxiety. HDL cholesterol over 1 or 6 months. Moreover, curcumin
Diabetic encephalopathy is characterized by impaired in physiological concentration of 2 lmol/L was reported to
cognitive functions and neurochemical structural abnor- induce the expression of ABCG1 in the human hepatoma
malities, which involves directly in neuronal damage cell line HepG2, thus increasing HDL-dependent lipid
caused by intracellular glucose. Curcumin (60 mg/kg) efflux and plasma HDL cholesterol levels [72]. In addition,

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158 Eur J Nutr (2011) 50:151–161

hyperglycemia leads to increased oxidative stress resulting discontinued curcumin after a few days to 2 weeks due to
in endothelial dysfunction. A randomized, parallel-group, intractable abdominal fullness or pain, and the dose of
placebo-controlled, 8-week study was performed to eval- curcumin was reduced to 4,000 mg/day because of
uate the effects of NCB-02 (a standardized preparation of abdominal complaints in 2 other patients [77].
curcuminoids), atorvastatin, and placebo on endothelial According to a joint report of the Food and Agriculture
function and its biomarkers in patients with type 2 diabetes Organization and the World Health Organization on food
mellitus. In this study, 72 patients with type 2 diabetes additives, the recommended maximum daily intake of
were randomized to receive NCB-02 (two capsules con- curcumin is 0–1 mg/kg body weight, but several clinical
taining curcumin 150 mg twice daily), atorvastatin 10 mg studies dealing with its efficacy suggested that it is safe and
once daily, or placebo for 8 weeks. NCB-02 had a favor- well tolerated even when intake is as high as 12 g/day [10,
able effect, comparable with that of atorvastatin, on 78]. However, apparent side effects have been reported
endothelial dysfunction in association with reductions in thus far. Gastrointestinal upset, chest tightness, inflamed
inflammatory cytokines and markers of oxidative stress. skin, and skin rashes are said to occur with high doses. A
Patients receiving NCB-02 showed significant reductions few cases of allergic contact dermatitis from curcumin
in the levels of malondialdehyde, endothelin-1 (ET-1), have also been reported [79]. The chronic use of curcumin
IL-6, and TNFa [73]. Recently, the effect of curcumin has can cause liver toxicity, and individuals with hepatic dis-
been investigated in the activities of drug-metabolizing ease, persons misusing alcohol, and those who take pre-
enzymes such as CYP1A2, CYP2A6, N-acetyltransferase scription medications that are metabolized by liver should
(NAT2), and xanthine oxidase (XO) in 16 healthy male probably avoid curcumin. Curcumin is not recommended
Chinese volunteers, using caffeine as a probe drug. After for persons with biliary tract obstruction, because it stim-
14 days, in the curcumin-treated (1,000 mg/day) group, ulates bile secretion [80]. Nevertheless, the multifaceted
CYP1A2 activity was decreased by 28.6%, while CYP2A6 pharmacological nature of curcumin and its pharmacoki-
activity was increased by 48.9% [74]. Curcumin–phos- netics in obesity remains unknown and additional research
phatidylcholine complex (MerivaÒ) was evaluated in 50 is needed in this field.
patients with osteoarthritis at dosages corresponding to
200 mg of curcumin per diem. After three months of
treatment, C-reactive protein (CRP) levels decreased from Future prospects
168 ± 18 to 11.3 ± 4.1 mg/L in the subpopulation with
high CRP, while control group experienced only a modest In recent decades, a rapid increase in the costs of health
improvement in these parameters (175 ± 12.3 to care has increased the importance of naturally occurring
112 ± 22.2 mg/L) in the CRP plasma concentration. It has phytochemicals in plants for the prevention and treatment
been suggested that MerivaÒ is clinically effective in the of human diseases, including obesity. The modulation of
treatment of osteoarthritis and could be taken into consid- several cellular transduction pathways by curcumin has
eration for clinical use [75]. In addition, the same curcu- recently been extended to elucidate the molecular basis for
min–phosphatidylcholine complex has been investigated obesity and obesity-related metabolic diseases. Current
among inflammatory conditions such as chronic anterior knowledge suggests that the potential complementary
uveitis relapses in a 12-month follow-up clinical trial. effect of curcumin may occur through several mechanisms
Curcumin–phosphatidylcholine complex, Meriva (Norflo), including suppression of inflammatory proteins, uptake of
administered twice a day in 106 patients of recurrent glucose, stimulation of catabolic pathways in adipose tis-
anterior uveitis of different etiologies. The results showed sues, liver, and other tissues, inhibition of angiogenesis in
that Norflo was well tolerated and could reduce eye dis- adipose tissues, inhibition of differentiation of adipocytes,
comfort symptoms and visible effects after a few weeks of stimulation of apoptosis of mature adipocytes, and reduc-
treatment in more than 80% of patients [76]. Curcumin’s tion in chronic inflammation associated with adiposity.
ability to lower blood glucose and cholesterol and its Numerous studies confirm its potential role in vitro and in
antioxidant nature make it a potential therapeutic for the animals, yet further human studies, in particular clinical
treatment of obesity-related diseases. Recent evidence has trials, are required to confirm the therapeutic nature of
shown that curcumin plays a key role in the protection curcumin in obesity and insulin resistance. Expanded use
against various obesity-related cancers including pancre- of molecular technologies such as DNA microarrays and
atic cancer. Curcumin (8,000 mg/day) in concomitant proteomics will help to identify newly molecular targets of
administration with gemcitibine intravenously (1,000 mg/ curcumin and individuals at high risk of obesity-related
m/week) was observed in 17 patients of advanced pan- metabolic diseases. Future trials should also include suit-
creatic cancer for 4 weeks. Curcumin has a proven efficacy ably planned pharmacodynamic studies, because the
in patients, with the exception of a few patients (29%) who effective dose required for modulating these metabolic

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Eur J Nutr (2011) 50:151–161 159

responses is unclear at the present. It is important to note 17. Hajri T, Tao H, Wattacheril J, Marks-Shulman P, Abumrad NN
that high doses of curcumin in supplement form may have (2010) Regulation of adiponectin production by insulin: Inter-
actions with tumor necrosis factor-alpha and interleukin-6. Am J
adverse effects. At present, there is not sufficient data to Physiol Endocrinol Metab, doi:10.1152/ajpendo.00307
support recommending long-term, safe usage for the pre- 18. Moschen AR, Molnar C, Geiger S, Graziadei I, Ebenbichler CF,
vention and treatment of obesity. Future translational and Weiss H, Kaser S, Kaser A, Tilg H (2010) Anti-inflammatory
clinical research overlapping metabolism with the aim to effects of excessive weight loss: potent suppression of adipose
interleukin 6 and tumour necrosis factor alpha expression. Gut
unravel the role of curcumin in obesity-related comorbid- 59(9):1259–1264
ities is highly warranted. On behalf of such studies, one 19. Lofgren P, Van H, Reynisdottir VS, Naslund E, Ryden M,
might be able to gain insights into curcumin mechanisms at Rossner S, Arner P (2000) Secretion of tumor necrosis factor-a
a clinical level and assess, within a short period, the shows a strong relationship to insulin-stimulated glucose trans-
port in human adipose tissue. Diabetes 49(5):688–692
potential success or failure of long-term interventions. 20. Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6 K directly
phosphorylates IRS-1 on Ser-270 to promote insulin resistance in
Acknowledgments This work was supported by Nuclear Research response to TNF-(alpha) signaling through IKK2. J Biol Chem
and Development Program of National Research Foundation of Korea 283(51):35375–35382
funded by Ministry of Education, Science and Technology (grant 21. Emanuelli B, Eberle D, Suzuki R, Kahn CR (2008) Overex-
code: 2010-0017517). pression of the dual-specificity phosphatase MKP-4/DUSP-9
protects against stress-induced insulin resistance. Proc Natl Acad
Sci USA 105(9):3545–3550
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