Abstract

The incidence of obesity is increasing worldwide and is hence considered a major public health concern. Obesity underlies the development of several metabolic complications including cardiovascular diseases, diabetes, and inflammation. Research on ways to slow the development of obesity have traditionally focused on dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity. An area that has recently aroused considerable research interest is investigating the potential role of spices, particularly the Asian spice turmeric, for combating obesity. Curcumin is the active ingredient in turmeric. Evidence suggests curcumin may regulate lipid metabolism, which plays a central role in the development of obesity and its complications. The present review addresses the evidence and mechanisms by which curcumin may play a role in downregulating obesity and reducing the impact of associated problems.

INTRODUCTION

Obesity is increasing at an alarming rate worldwide and continues to be a major public health concern.1 In the United States, the prevalence of obesity in adults doubled between 1980 and 2004.2,3 Although the rates stabilized after 2004, one-third of Americans are still considered obese.3 Obesity is a major risk factor in the etiopathology of several health disorders including cardiovascular diseases, hypertension, hyperlipidemia, diabetes mellitus, and several types of cancers. Obesity and the aforementioned complications contribute to the development of metabolic syndrome.

Recent evidence has shown that some dietary components such as spices may play a key role in the protection against and/or treatment of obesity and related metabolic disorders. Among these spices, turmeric has received considerable research interest because of its active ingredient, curcumin. Turmeric is extracted from the rhizomes of Curcuma longa L. It is a popular spice in Asian cuisine and has been known to be beneficial for health.4 The therapeutic use of turmeric can be traced back to Indian Ayurvedic and traditional Chinese medicines.5 Increasing evidence from numerous in vitro and in vivo studies have shown that curcumin possesses anticancer, anti-inflammatory, antioxidant, and hypolipidemic properties.6,17 Most recently, its effects on obesity and related disorders have been under investigation. The present review focuses on the health benefits curcumin and its potential for use in the treatment of obesity and associated complications.

METABOLISM OF CURCUMIN

Curcumin, a hydroxycinnamic acid derivative,18 has two hydrophobic polyphenolic rings connected by two carbonyl groups. Metabolism of curcumin in the intestine involves sulfation, glucuronidation, and reduction reactions, which result in poor systemic absorption.19,20 These metabolites have a very short half life and poor cell permeability. Whether they are as bioactive as their parent compound is not yet well established.21

Finding ways to improve the systemic absorption of curcumin has been challenging. When cosupplemented with 20 mg of piperine (an alkaloid in black pepper), a 2,000% increase was found in the absorption of curcumin.22 However, piperine has some side-effects.22“Nanocurcumin”, a nanoparticle-based form of curcumin, has been developed to improve the solubility and bioavailability of curcumin; in vitro, it has been effective for retrogressing inflammatory responses and promoting apoptosis in human pancreatic cancer cell lines.23 When curcumin formulated with phosphatidylcholine was given to male Wistar rats, a fivefold increase in the plasma level of curcumin was noticed.24 Another study showed that when administered with olive oil, stearic acid, or phosphatidyl choline, the level of curcumin in blood increased.20 It was also found that turmeric spice added to a food matrix containing oil increased the bioavailability of curcumin.25 In an in vivo experiment performed with murine models, administration of a combination of curcumin and lipids resulted in curcumin serum levels that were 50 times higher, which was found to be effective for ameliorating neuro-inflammatory and Alzheimer's diseases.26

So far, an upper level of toxicity has not been established for curcumin. Studies have shown that a dosage as high as 12 g/day is safe and tolerable to humans with a few reporting mild side-effects.27,29 Among the reported side-effects is its possible role in iron chelation. Jiao et al. reported curcumin to be an active iron chelator, which can intensify iron deficiency in people with low iron stores, cancer, or other chronic diseases.30 Curcumin attenuates hepcidin biosynthesis, a regulatory protein involved in iron transport.30

ROLE IN LIPID METABOLISM

A recently published study has demonstrated the hypolipidemic effect of curcumin by lowering both triglycerides (TG) and free fatty acids in the plasma of high-fat-fed hamsters.31 In another study, dietary curcumin effectively reduced the elevated serum and hepatic TG concentration in high-fat-fed rats.27 In a study in which capsaicin (an active component in red pepper) was tested as a treatment to lower blood cholesterol in high-fat-fed rats, it was found to be ineffective27; however, it was found to be quite effective in conjunction with dietary curcumin.27

Feeding curcumin (1% w/w) to mice significantly lowered their liver TG levels,32 which suggests this might prove to be a useful therapeutic strategy for treating fatty liver disease associated with hyperlipidemia and obesity.32,33 When high-fat-fed rats were put on a curcumin-supplemented diet, there was a significant decrease in the TG content of VLDL but not of chylomicrons.6,34 This implies that curcumin promotes hepatic TG clearance without interfering with intestinal TG absorption.34 It has been proposed that curcumin and its metabolites function as peroxisome proliferator-activated receptor (PPARγ)-activating ligands, thus explaining their action as hypolipidemic agents.34 The hypolipidemic effect of curcumin has also been found to be effective at treating diabetic nephropathy in rats.35

Curcumin, by suppressing the hepatic enzymes HMG-CoA reductase and Acyl CoA cholesteryl acyl transferase (ACAT), lowers the hepatic cholesterol, total cholesterol, and non-high-density lipoprotein (HDL)-C levels.31 The same study also reported that curcumin supplementation inhibited hepatic fatty acid synthase (FAS) activity and increased beta oxidation of fatty acids. Curcumin has been shown to specifically downregulate FAS,36 leading to an effective decrease in fat storage. However, curcumin's effect on FAS activity is not well established.34

Upregulation of the fatty acid oxidation can also reduce the fat depots in obese individuals. By diminishing the mRNA expression of glycerol-3-phosphate acyl transferase-1 in a dose-dependent manner, curcumin reduces the accumulation of lipids in adipocytes.33 At the same time, curcumin stimulates fatty acid oxidation by increasing the carnitine palmitoyltransferase-1 mRNA expression.33 The AMP-activated kinase (AMPK) activation by curcumin resulted in phosphorylation of acetyl CoA carboxylase, thereby making acetyl coenzyme A (CoA) unavailable.33 Acetyl CoA is essential to synthesize malonyl CoA, the important precursor for fatty acid synthesis.

Jang et al.31 noticed a significant increase in plasma Apo-A-1, HDL particles, and paraoxonase (PON) levels with curcumin supplementation in high-fat-fed hamsters. Paraoxonases are hydrolytic enzymes with several isoforms: PON1, PON2, and PON3.37 PON1 is present only in liver, while PON2 is a ubiquitous intracellular antioxidant.37,38 PON1 and PON3 are both associated with HDL and prevent the formation of oxidized LDL.37

In summary, there is substantial evidence to suggest curcumin is effective at inhibiting lipid synthesis and storage and stimulating fatty acid degradation. These effects are mediated by regulating the activities of several key enzymes and the expression of transcription factors that regulate lipid metabolism.

ROLE IN WEIGHT LOSS

Dietary therapy with curcumin in ob/ob mice resulted in significant weight loss and an increase in lean tissue mass.39 The inhibition of key transcriptional proteins involved in adipogenesis might explain the weight loss and the decrease in adipose tissue seen in curcumin-fed C57/BL mice.33 Previous studies have also reported a reduction in the levels of pro-inflammatory cytokines and C-reactive proteins (CRPs) along with increases in weight loss.40,41 Evidence from in vitro and in vivo studies in high-fat-fed mice demonstrated that curcumin supplementation (500 mg/kg diet) can increase the basal metabolic rate, thereby contributing to increased energy expenditure and weight loss.33 Loss of body weight and increase in the percentage of lean mass are extremely beneficial toward decreased insulin resistance and improved cardiovascular health in obese people.33,39

Thus, there is evidence to suggest that in addition to its effect on lipid metabolism, which lowers TG synthesis and increases fatty acid oxidation, curcumin may also reduce body weight by increasing the basal metabolic rate and the release of some cytokines.

ROLE IN CARDIOVASCULAR DISEASE

Curcumin may play a crucial role in regressing atherosclerosis. When ApoE/LDLR double knockout mice fed with a Western-style diet were given oral supplementation with a low dose of curcumin (0.3 mg/day/mouse), there was notable decrease in atherosclerotic lesions. The outcome of this study is particularly relevant in light of the poor systemic absorption of curcumin42 and high prevalence of atherosclerosis in obese people. It has been proposed that the observed antiatherogenic effect of curcumin was not due to the altered lipid metabolism but rather due to its effect on the development of atherosclerotic lesions.42 Curcumin has been shown to have antiproliferative effects on vascular endothelial cells.43 Its inhibition of hypertrophy-inducing transcription factors, like p300-histone transacetylase, averts the development of myocardial hypertrophy and heart failure in animal models.43,44

In addition, curcumin may influence key enzymes necessary for the proper functioning of the cardiovascular system, such as nitric oxide synthase (NOS). Curcumin downregulates NOS expression.45,46 Since nitric oxide-mediated oxidative stress has been associated with chronic diabetes, downregulating NO production could be beneficial in treating cardiovascular complications.47,49 The effective reduction in NO by curcumin is thought to be mediated by NFκB, AP-1, and various vasoactive factors.46

Heme oxygenase-1 (HO-1), a stress-induced protein, has been known to protect cells against oxidative stress.50 HO-1 restricts tissue damage in response to proinflammatory stimuli and protects endothelium during atherogenesis.50,51 Stimulating HO-1 production has been shown to inhibit the progression of atherosclerosis in Apo-E-deficient mice.52,53 It has been demonstrated in vitro that curcumin could induce HO-1 through the activation of Nrf2-dependent antioxidant response element in endothelial cells.43,54 Although not confirmed, it is possible that curcumin's antiatherogenic effect may be due to its ability to induce HO-1.50

To summarize, there is ample evidence to suggest curcumin offers protection from cardiovascular diseases by reducing atherosclerotic lesions, inhibiting vascular endothelial cell proliferation, reducing NO production, and inducing HO-1 enzyme.

ROLE IN DIABETES AND INSULIN RESISTANCE

Type 2 diabetes mellitus (T2DM) is intimately associated with obesity.55 The impaired insulin sensitivity seen with obesity is thought to be due to the presence of high concentrations of free fatty acids in plasma and tissues.56,57 High levels of pro-inflammatory cytokines in the blood can be seen in insulin resistance associated with obesity and T2DM.58,59 The lipid-induced insulin resistance in obesity is mainly due to the free fatty acid-mediated activation of nuclear factor kappa B (NFκB) and other signaling pathways.55,60 Evidence shows that NFκB plays a critical role in the development of insulin resistance.61,62 Activation of the NFκB pathway causes overproduction of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 from 3T3-L1 adipocytes.55 TNF-α and IL-6 can disturb the transcriptional activity of insulin receptors (insulin receptor substrate-1, IRS-1) and protein transporters, such as glucose transporter-4 (GLUT-4).55,64 The impaired insulin signaling results in insulin resistance.63

Experimental studies suggest curcumin is an effective anti-diabetic agent.65,66 Data also suggest curcumin's role in glucose homeostasis is mediated through its activation of glycolysis, inhibition of hepatic gluconeogenesis, and reduction of lipid metabolism.67 Oral curcumin supplementation was found to be effective for treating hyperglycemia seen in genetically diabetic KK-Ay mice and streptozotocin-induced diabetic rats.65,68 Another study performed with high-fat-fed hamsters established that curcumin improved insulin sensitivity, as illustrated by lower insulin resistance index values.31

Curcumin's role as an NFκB inhibitor is thought to participate in mitigating insulin resistance.55 Curcumin demonstrates hypoglycemic effects by activating PPARγ, thereby inhibiting increases in blood glucose levels.66 Increased levels of endoplasmic reticulum (ER) stress in adipose and liver tissue is associated with obesity.39 Compounds that can alleviate this stress have been found to improve insulin resistance and glycemic status in obesity mouse models.39 Curcumin caused a reduction in ER stress with increased gene expressions of Sirtuin 1(Sirt1), heat shock proteins, and transcription factors like Forkhead box O (FOXO) proteins.39

Curcumin has been shown to prevent the formation of advanced glycation end-products and collagen cross-linking in diabetic rats.69 Oral curcumin therapy in genetically obese Lepob/ob mice resulted in a significant decrease in hemoglobin A1c percentage and improved insulin sensitivity.39 The use of synthetic curcumin analogs like ferulamides has been suggested for treating hyperglycemia associated with metabolic syndrome.70

Evidence suggests curcumin may be a good antidiabetic agent. It reduces free fatty acids and cytokine release, inhibits NFκB, and reduces insulin resistance by controlling hyperglycemia.

CURCUMIN IN INFLAMMATION

Inflammation is an integral component of many obesity-associated complications. Macrophage invasion mediated by monocyte chemoattractant protein-1 plays a key role in inflammation development and the release of TNF-α from adipose tissue.39,72 Signals from TNF-α receptors and Toll-like receptors of macrophages activate NFκB in differentiated adipocytes.21 Increased expression of TNF-α genes in adipocytes induces lipolysis, enhances cytokine release, and promotes insulin resistance.21,75 Obesity increases the release of proinflammatory cytokines like IL-6 from adipose tissue.76,77 Elevated serum levels of IL-6 increase hepatic synthesis of CRP,77,78 which is considered a risk for cardiovascular disease.77,79

Evidence indicates that low-grade chronic inflammation due to cytokine release from adipose tissue plays a significant role in intensifying the inflammatory elements of obesity-linked cardiovascular diseases and insulin resistance.21 Increased body mass index seen with obesity has been found to be associated with elevated serum levels of proinflammatory mediator prostaglandin E2.73,81 Deletion of pro-inflammatory genes in obese mouse models hindered the development of insulin resistance and hyperglycemia.82,84

Curcumin has therapeutic effects in inflammation-mediated diseases.85,87 It has been shown to inhibit activation of the c-Jun N-terminal kinase (JNK) pathway and expression of NFκB p65, thereby downregulating the proinflammatory responses.55,91 It also suppresses macrophage activation and infiltration into adipose tissue.39,92 Curcumin inhibits the phosphorylation of protein IκB kinase (IKK), thereby inhibiting NFκB translocation to the nucleus.21,94 Significant decreases in TNF-α, interleukin-1 β (IL-1β), IL-6, and cyclooxygenase-2 gene expression have also been noted with curcumin treatment.21 Reduction in IL-1β expression is especially significant as this guarantees the functionality of insulin receptor substrate-1 (IRS-1) in adipocytes.21

It has been suggested that curcumin and other turmeric extracts are potent PPARγ agonists that thereby mediate differentiation of adipocytes.66 However, emerging evidence shows curcumin is unable to either stimulate PPARγ or induce differentiation of preadipocytes.95 More support for this hypothesis was found in a recent study that revealed curcumin induces the activation of AMPK followed by PPARγ inhibition.96 AMPK inhibits activation of such main transcription factors as PPARγ and CCAAT/ enhancer binding protein a (C/EBP) involved in adipogenesis.33 Activated AMPK, an upstream regulator of PPARγ in 3T3-L1 adipocytes, is found to be an inhibitor of adipocyte differentiation.96 Curcumin-induced AMPK-mediated inhibition of adipocyte proliferation has great clinical significance in the treatment of obesity because AMPK has been implicated in maintaining cellular energy balance and adipocyte apoptosis.96,98

Adipose tissue secretes several adipokines; the ones studied most commonly are adiponectin and leptin. When obesity develops, there is a decrease in adiponectin but an increase in leptin secretions. The role of curcumin in modulating adiponectin may be mediated through its action on PPARγ. PPARγ plays a crucial role in adipocyte differentiation and the expression of many adipocyte-specific genes.18 PPARγ forms a heterodimeric complex with retinoid X receptor-α (RXR-α) transcription factor and controls the genetic expression of adiponectin.99 The NFκB–PPARγ complex prevents PPARγ binding to DNA, thereby limiting PPARγ functions.100 Inhibition of PPARγ lowers serum adiponectin concentration. Plasma adiponectin level was found to be lower in obese and insulin-resistant individuals.101,103 Reduced adiponectin mRNA expression associated with NFκB-mediated oxidative stress also results in lower amounts of circulating adiponectin.61,104 Adiponectin-deficient mice have been shown to develop insulin resistance.102 Moreover, adiponectin treatment has been shown to relieve insulin resistance in obese mice.103

Therefore, increasing adiponectin secretion is a potential therapeutic target for treating obesity and T2DM.18 Evidence suggests curcumin induces adiponectin secretion105 by inhibiting the NFκB pathway.106 Curcumin treatment enhances adiponectin mRNA expression.39 Similar to curcumin, hydroxycinnamic acid derivatives, caffeic acid phenethyl ester, and trans-ferulic acid have been shown to increase serum adiponectin secretion in 3T3-L1 adipocytes by inhibiting the NF-κB activation pathway.18 Another possible mechanism by which adiponectin secretion can be increased is to enhance the expression of Sirt1 genes, which, in turn, activates the FOXO proteins.39,107 Proteins like Sirt1 and FOXO were found to be diminished in obese mice and curcumin treatment reversed this reduction.39,108

Adiponectin-induced activity of synthetic compounds like N-arylalkylferulamides (structural similarities to curcumin), has also been reported.70 Like curcumin, these highly active compounds activate PPARγ and stimulate the adiponectin gene expression in 3T3-L1 cells and human pre-adipocytes.70 Although there was no significant increase in the serum adiponectin level, these compounds decreased blood glucose and triglyceride levels in diabetic KK-Ay /Ta mice.70 The exact mechanism of this ferulamide action is not clear.70

Another adipokine found to be associated with obesity is leptin. Circulating levels of leptin are directly proportional to the amount of body fat; they are also involved in energy homeostasis. The high level of leptin associated with obesity is lowered by curcumin supplementation. This could be due to the action of curcumin on plasma TG and fatty oxidation.31 Thus, there is sufficient evidence to suggest that curcumin reduces inflammation by regulating the inflammatory mediators such as cytokines and adipokines through its action on some signal transduction pathways.

CURCUMIN AS AN ANTIOXIDANT

Oxidative stress is associated with increases in body mass index.77,110 Accordingly, obese people can be considered to be under great oxidative stress.77,111 Elevated inflammatory responses in obese individuals can also increase the oxidative stress in adipose tissue.77 Plasma biomarkers of oxidative stress and F2-isoprostanes are elevated in subjects with atherosclerosis and hypercholestremia.77,113 Treatment with antioxidants like vitamin E has been effective at lowering the high F2-isoprostanes levels in hypercholesteremic individuals.77,114

Numerous in vitro and in vivo studies have demonstrated the antioxidant properties of curcumin. Activator protein-1 (AP-1) belongs to a group of transcription factors that are activated in response to stress, growth factors, cytokines, and infections.115 Curcumin as an antioxidant can inhibit the stress-stimulated activation of AP-1.89 Curcumin and its metabolite, tetrahydrocurcumin, have been shown to improve oxidative stress-induced renal injury in mice.116 Supplementation with curcumin also reduced the effects of oxidative stress associated with traumatic brain injury in high-fat-fed rats.117 Curcumin can also increase the antioxidant vitamin levels, which are depleted due to high-fat-diet-induced oxidative stress.27,118 This antioxidant property could be beneficial for protecting against the development of diabetes in obese individuals. A study of diabetic rats showed that curcumin increased the activity of the antioxidant enzyme glutathione peroxidase and decreased oxidative stress.15,119

Hyperlipidemia seen with obesity or the prolonged intake of a high-fat diet affects membrane fluidity and the structural integrity of red blood cells.120,121 Studies of hypercholesteremic rats have shown that curcumin wards off any changes in the membrane's cholesterol-to-phospholipid ratio as well as antioxidant levels in red blood cells.6,7 The hypocholesteremic effect of curcumin leads to reduced cholesterol content in the membranes.7,122 Curcumin has also inhibited lipid peroxidation in the red blood cells and liver of high-fat-fed hamsters.31 The decrease in lipid peroxidation in liver microsomes and mitochondria proved to be protective in atherosclerotic rabbits.123 Increases in the super oxide dismutase and cytochrome C reductase activity, together with high hepatic lipid peroxide content seen in high-fat-fed rats, were offset by curcumin treatments.6

Curcumin supplementation (200 mg/kg body weight) in diabetic rats also led to a decline in lipid peroxidation.69 Dietary curcumin successfully reversed the diminished hepatic glutathione reductase and glutathione peroxidase enzymes and annulled the increase in lipid peroxide content.43,124 Similar effects for curcumin were reported in other antioxidant enzymes.27,126 The activities of serum antioxidant enzymes such as glutathione transferase and glutathione peroxidase were also increased with curcumin treatment in high-fat-fed rats.27,124 Enhancing the activities of these antioxidant enzymes plays a major role in the antioxidant and anticarcinogenic activities of curcumin.27,127 Curcumin also reduces oxidative stress by reducing peroxide formation and increasing antioxidant enzyme activities.

CONCLUSION

The studies presented in this review demonstrate curcumin has a potential role to play in efforts to decrease the incidence of obesity and its associated risk factors, mainly because of its anti-inflammatory and antioxidant properties (Figure 1). Curcumin has also been shown to be beneficial in aiding glycemic control in diabetics, further enhancing its role in cardiovascular disorders. Limited absorption from the diet128 and the resulting poor systemic availability have been major factors limiting the use of curcumin as a therapeutic agent.20,129 Recent studies have shown promise for the potential discovery of an inhibitor that blocks the rapid degradation of curcumin in the intestine.21 Developing synthetic curcumin analogs that have a prolonged in vivo half-life may present an alternative approach.21,105 Such research activities could lead to the use of curcumin and its derivatives in the treatment of various obesity-related disorders.

Figure 1

Curcumin modulates pathways responsible for obesity-related complications.Abbreviations: +, indicates activation; −, indicates inhibition or reduction; +/−, indicates activation or inhibition.

Figure 1

Curcumin modulates pathways responsible for obesity-related complications.Abbreviations: +, indicates activation; −, indicates inhibition or reduction; +/−, indicates activation or inhibition.

Declaration of interest

The authors have no relevant interests to declare.

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