|Year : 2012 | Volume
| Issue : 2 | Page : 63-76
Nutraceuticals in pathogenic obesity; striking the right balance between energy imbalance and inflammation
Sunil K Kota1, Sruti Jammula2, Siva K Kota3, Surabhi Venkata Satya Krishna1, Lalit K Meher4, Epari Sanjeeva Rao5, Kirtikumar D Modi1
1 Department of Endocrinology, Medwin Hospital, Hyderabad, Andhra Pradesh, India
2 Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India
3 Department of Anesthesia, Central Security Hospital, Riyadh, Saudi Arabia
4 Department of Medicine, MKCG Medical College, Berhampur, Orissa, India
5 Department of Pathology, KIMS Research & Foundation, Amalapuram, Andhra Pradesh, India
|Date of Web Publication||22-Sep-2012|
Sunil K Kota
Resident in Endocrinology, Department of Endocrinology, Medwin Hospitals, Chiragh Ali Lane, Nampally, Hyderabad - 500001, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Obesity leads to chronic, excessive adipose tissue expansion resulting in an increase in the risk for cardiovascular disease, type 2 diabetes mellitus, and other metabolic abnormalities. This is primarily thought to stem from the low-grade, systemic inflammatory response syndrome that characterizes adipose tissue in obesity. With a global increase in the prevalence of obesity, nutrition and exercise play a key role in its prevention and treatment. Natural product (nutraceutical) interventions are currently being investigated on a large-scale basis as potential treatments for obesity and weight management. Apart from taking care of the imbalance between energy intake and energy output, nutraceuticals should have the potential to ameliorate the development of oxidative stress and inflammation in obesity, thereby limiting the onset of obesity complications. The current article aims to examine current research on nutraceuticals and their role in the management of obesity and body composition.
Keywords: Adipose tissue, inflammation, nutraceuticals, obesity
|How to cite this article:|
Kota SK, Jammula S, Kota SK, Satya Krishna SV, Meher LK, Rao ES, Modi KD. Nutraceuticals in pathogenic obesity; striking the right balance between energy imbalance and inflammation. J Med Nutr Nutraceut 2012;1:63-76
|How to cite this URL:|
Kota SK, Jammula S, Kota SK, Satya Krishna SV, Meher LK, Rao ES, Modi KD. Nutraceuticals in pathogenic obesity; striking the right balance between energy imbalance and inflammation. J Med Nutr Nutraceut [serial online] 2012 [cited 2019 Mar 24];1:63-76. Available from: http://www.jmnn.org/text.asp?2012/1/2/63/101288
| Introduction|| |
Obesity is a major global health epidemic of the 21 st century. It continues to plague the world at an alarming rate with approximately 1.5 billion adults classified as overweight with a third being obese in 2008.  The number is expected to increase over the next 5-10 years. It is also predicted that by the year 2015, 2.3 billion adults would be overweight and >700 million of them would be obese.  The growing prevalence of obesity is associated with significant metabolic complications like type 2 diabetes, hyperlipidemia, hypertension, and cardiovascular disease (CVD) causing substantial socioeconomic and physical burden on society. ,
| The Regulatory Control System|| |
Normal food intake is a well balanced system between energy intake and output, which when gets disturbed culminates into weight gain and obesity [Figure 1]. The feedback system regulating body weight and appetite is the target of ongoing intense research with appreciation of the complexity of this system increasing as new modulators and players are identified.
Gastric distension via activation of vagal afferents is a signal for satiety, with gastric contractions signaling for hunger. Nutrients, neural impulses, and hormones themselves act as afferent signals in the regulation of energy intake and expenditure. Nutrient absorption of glucose  initiates a sensation of satiety whereas a fall in glucose promotes hunger. This effect is itself mediated by different neurotransmitters, hormones, and peptides. Leptin  is a peptide produced by adipocytes, with secretion increasing as fat deposition increases. It acts to reduce food intake and is believed to increase sympathetic nervous system activity.  Another important peptide is growth hormone (GH) relin, which is secreted by the stomach and duodenum and stimulates GH secretion. It is an endogenous ligand for the GH receptor. GH relin increases food intake and its secretion is in turn suppressed by food intake. ,, Serum concentrations increase in anticipation of a meal. Its secretion increases after diet- and exercise-induced weight loss and is believed to be one of the reasons why lifestyle modification does not lead to permanent weight loss.
Other peptides that have been shown to reduce food intake are cholecystokinin (CCK), enterostatin, and polypeptide Y 3-36. ,, The list of peptides is ever on the increase but the precise interaction between them and their relevance in humans awaits the outcome of further research [Figure 2].
|Figure 2: Monoamines and peptides affecting feeding AgRP- Agouti related peptide, GH- Growth hormone, CART- Cocaine amphetamine related transcript, MSH- Melanocyte stimulating hormone, GLP-1- Glucagon like peptide 1|
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Central processing unit
Afferent impulses proceed centrally to the hindbrain and the hypothalamus for integration and processing.  The nucleus of the tractus solitarius in the hindbrain is the site where vagal and other neural inputs are integrated. The arcuate nucleus at the base of the hypothalamus receives signals from leptin and in turn increases both production and secretion of neuropeptide Y (NPY) and Agouti- related peptide (AgRP) thereby increasing food intake. Furthermore, cocaine-amphetamine-related transcript (CART) and pro-opiomelanocortin (POMC) decrease food intake. [Figure 3]
|Figure 3: Overview of integrated regulatory pathway NPY- Neuropeptide Y, AgRP- Agouti related peptide, VM- Ventromedial, MSH- Melanocyte stimulating hormone, MC- melanocortin|
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Serotonin (5-HT) acts via postsynaptic 5- HT 1B receptors on para ventricular nucleus (PVN) of hypothalamus to reduce food intake.  The hypophagic actions of 5-HT may be mediated at least partly through the NPY pathway.
Corticotrophin releasing factor (CRF) which also causes weight loss by reducing appetite and act in opposing to NPY on the regulation of energy balances. CCK, a neurotransmitter present in the brain plays a physiological role as a meal termination (satiety) signal between the two receptors such as CCKA and CCKB, CCK acted at CCKA receptors. 
The hypothalamic PVN is itself stimulated by peptides from arcuate nucleus and relays signals further. Ventromedial hypothalamus promotes appetite, whereas the lateral hypothalamic nucleus promotes satiety. Furthermore, specific areas of the amygdale can affect feeding partially through the ventromedial hypothalamus.
The peripheral nervous system has a definite role in stimulating thermogenic tissues via activation of beta 3 adrenergic receptors resulting in a reduction in food intake.  The sympathetic nervous system plays a tonic role in maintaining energy expenditure. Glucocorticoids play an permissive role at the efferent end of the regulatory system, mediated via the sympathetic nervous system.  For example, it has been noted that leptin deficiency does not result in obesity in the absence of glucocorticoids.
| Role of Inflammation|| |
Obesity is accompanied by adipose tissue hyperplasia and hypertrophy. The adipose tissue serves as an important initiator of a chronic low grade systemic inflammatory response.  This is characterized by infiltration of macrophages and other immune cells with subsequent release of proinflammatory cytokines like interleukin-1 (IL-1), tumor necrosis factor-a (TNF α), plasminogen activator inhibitor-1, leptin, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), retinol binding protein- 4(RBP-4), macrophage inflammatory protein (MIP). ,, All these mediators lead to deranged insulin sensitivity, dysregulated energy, and vascular system homeostasis. Macrophage infiltration and inflammation in other organs like liver and skeletal muscle further contribute to insulin resistance.  Furthermore, plasma levels of vitamins and antioxidants are lower in the obese  and an inverse relationship has been shown between serum total antioxidant capacity and waist circumference.  Research also indicates the modulatory effects of vitamins and antioxidants on the immune system  and these reduced levels have a role in the development of inflammation and ultimately disease, in obesity.
Pharmacological approaches and various surgical procedures at disposal are associated with shear expenses. Nutritional strategies aimed to reduce positive energy balance by decreasing energy intake, increasing energy expenditure, and suppressing the inflammatory excursions seem to be a very logical and attractive alternative. A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease.  These in combination with the lowering of saturated fats, and exercise intervention may hold the key to the treatment of the metabolic syndrome which is plaguing much of the world today.  The current article reviews the nutraceutical agents for obesity treatment. [Table 1] gives an overview of common antiobesity nutraceutical plant preparations in India.
Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent for health care, preservation of food, and as a yellow dye for textiles. Curcumin is the pigment imparting yellow color to turmeric.
Mechanism of action
- It down regulates the expression of various nuclear factor kappa B (NF-kB)-regulated proinflammatory adipokines, including chemokines (MCP-1, MCP-4, and eotaxin) and interleukins (IL-1, IL-6, and IL-8) in vitro. ,
- There is suppression of the expression of PAI-1 by inhibiting the transcription factor early growth response (Egr-1), which has been closely linked with insulin resistance and obesity. 
- Curcumin suppresses oxidative stress induced loss of function of endothelial reticulum protein-folding enzyme; protein disulfide isomerase. It thereby reduces accumulation of misfolded proteins in the cell. 
- Ingestion of curcumin leads to reduced macrophage infiltration in white adipose tissue (WAT), increased adipose tissue adiponectin production, decreased hepatic NF-kB activity, and reduced the expression of hepatic inflammation markers, including TNF-α, IL-β, suppressor of cytokine signaling 3, MCP-1, and C-C motif receptor-2.
Taken together, these data suggest that curcumin may be a useful phytochemical for attenuating obesity-induced inflammation and obesity-related metabolic complications. For general use including weight loss, most practitioners recommend the following doses:
- Animal studies have shown that curcumin administration ameliorated diabetes in obese and leptin-deficient ob/ob C57BL6/J mice, as indicated by glucose- and insulin-tolerance testing and the percentage glycosylated hemoglobin. 
- Jain et al. reported that curcumin supplementation lowered the high glucose-mediated monocyte production of inflammatory cytokines, including TNF-α, IL-6, IL-8, and MCP-1. This same study also showed that blood levels of TNF-α, MCP-1, glucose, and glycosylated hemoglobin were decreased in diabetic rats on a curcumin diet. 
- Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis in adipocytes and obesity in C57/BL mice. The suppression of angiogenesis is by reduced expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Curcumin increases 5 AMP-activated protein kinase phosphorylation, reduced glycerol-3-phosphate acyl transferase-1, and increased carnitine palmitoyltransferase-1 expression, which led to increased oxidation and decreased fatty acid esterification in adipose tissue. The curcumin suppression of angiogenesis in adipocytes together with its effect on lipid metabolism in adipocytes may contribute to lower body fat and body weight gain. 
- Standardized curcumin powder: 400 to 600 mg three times daily
- Tincture (1:2): 15 to 30 drops up to four times daily
- Liquid extracts (1:1): 30 to 90 drops daily
Capsaicin, a biologically active ingredient found in red chili peppers. Capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers, probably as deterrents against certain herbivores and fungi. Pure capsaicin is a hydrophobic, colorless, odorless, and crystalline to waxy compound.
Mechanism of action
- There is alteration of thermogenesis and lipid metabolism-related proteins in white adipose tissue and skeletal muscle. , Thereby it induces thermogenesis and fat oxidation.
- There is increased energy expenditure by its action on sympathetic nervous system. The increased body temperature impacts upon satiety by the thermic effect of food.
- Augmented oxygen consumption increases metabolic rate leading to increased energy expenditure.  Upregulation of uncoupling protein 1 (UCP 1) in adipose tissue further contributes to thermogenesis.
- It has appetite regulator activity. 
- Additional antiinflammatory activity is also demonstrated. It reduces the expression of TNF-a and other inflammatory adipocytokines, such as IL-6 and MCP-1, in obese adipose tissue and isolated adipocytes by modulating the proinflammatory transcription factors NF-kB and peroxisome proliferator-activated receptor γ (PPAR γ). 
- Several studies have shown potential benefits of capsaicin for treating obesity and insulin resistance in animal models and clinical studies ,
- Capsaicin was shown in animal studies to increase the insulin-stimulated uptake of glucose in muscle cells 
- Zhu et al. have demonstrated that activation of transient receptor potential vanilloid type-1 (TRPV1) by capsaicin prevents adipogenesis. 
The exact amount found to be effective is between 8 and 25 micromoles of capsaicin per day. These results indicate that capsaicin may be useful for the treatment of obesity-related inflammatory metabolic dysfunctions.
Conjugated linoleic acid
Conjugated linolenic acid (CLA) is found primarily in the seeds of flax, and nut oils, as well as fish, and more readily in poultry eggs. CLA is very sensitive to temperature change and should not be used to cook food. It should rather be administered in its original state in salad dressings or taken as a therapeutic dosage.
Mechanism of action
- The amelioration of LDL/HDL concentrations in blood is one of the main beneficial actions. This is accomplished by lowering plasma triacylglycerol via the decrease of VLDL/apolipoprotein B production. [ 44]
- It manipulates the genetic expression of certain adipocytokines, modifying their proliferation or differentiation. These factors include CCAAT/enhancer binding protein, PPARy and other adipose-specific genes. 
- Melatonin (MLT) actually controls circadian rhythm in the human body. As such, when CLA, MLT, and eicosapentanoic acid (EPA) were administered to rodents, it was observed that fatty acid uptake was inhibited.  Additionally, cyclic amp (c-amp) was inhibited and this would allow for fat to be used as a primary source of energy. Thus CLA combined with melatonin may have a major impact on weight reduction.
- Supplementation of CLA reduced fat mass of obese individuals. 
- In one specific study, multiple dosages were experimented with, which included placebo (9 g olive oil), and dosages of up to 6.8 g of CLA. A reduction of fat mass was observed to be significant with the 3.4 g (P = 0.05) and 6.8 g (P = 0.02) groups, respectively. However, it should be noted that no greater amount of fat mass was noticed when the dosage was higher than 3.4 g, respectively. 
- In a recent study it has been shown that adding CLA to a high fat diet fed to rodents actually prevented the onset of obesity-induced muscle insulin resistance. 
However, what may be problematic is that there have been few clinical evaluations on humans.  Thus it is important to further explore the mechanisms and evaluate further weight loss in humans.
Polyunsaturated fatty acids
Fatty acids (FAs) can function as endogenous ligands that modulate inflammatory responses. Saturated FAs promote inflammation by activating toll-like receptor 4 (TLR4) on fat cells and macrophages and unsaturated FAs are weakly proinflammatory or neutral.  However, ω-3 polyunsaturated fatty acids (PUFAs) from fish oils, such as docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA), are known antiinflammatory factors.  These agents suppress obesity mediated activation of inflammation.
Mechanism of action
- The ω-3 fatty acids DHA, EPA sense G protein-coupled receptor 120 (GPR120), which is highly expressed in adipose tissue macrophages and fat cells. The activation of this receptor by DHA attenuates the proinflammatory effects of TNFa, IL-6, and Lipopolysaccharide on macrophages. 
- Activation of GPR120 by ω-3 fatty acids induces potent insulin sensitization and other antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
- In addition, PPARγ activation by long chain ω-3 PUFA has been implicated in the prevention of high-fat diet induced adipose tissue inflammation and remodeling. 
- Docohexaenoylethanolamine (DHEA), the ethnaolamide metabolite of DHA, modulates inflammation by reducing MCP-1 and nitric oxide (NO) production in macrophages. 
- Sekiya et al. have demonstrated that PUFA markedly decreased the mature form of sterol regulatory element-binding protein (SREBP-1) protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPAR a activators. They concluded that PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPAR a. 
- Robinson et al. have demonstrated that dietary n-3 polyunsaturated fatty acids modulate each of the components of the triad of adiposity, inflammation, and fatty acid metabolism, with particular attention to the role of the postprandial period as a contributor to the pathophysiology of metabolic syndrome. 
In conclusion, fish oil supplements can alleviate metabolic disease by modulating inflammatory signaling pathways.
Psyllium fiber is extracted from the husks of its seeds. These seeds are used commercially for the production of mucilage.
Mechanism of action
- Psyllium delays gastric emptying and depresses appetite.  Fiber may expand in the intestinal tract and as a result the body may feel more satiated.
- Psyllium fiber has a lower glycemic index, which has been found to decrease postprandial insulin and glycemic response. Psyllium fiber decreases the rate glucose of absorption. It traps glucose, and slows its absorption.
- It is a hydrophilic polysaccharide mucilage swelling several times its own weight in water and in the gastro-intestinal tract where by sheer bulk it stimulates peristalsis.
- The emollient nature of the bulk facilitates speedy passage through digestive system to reduce absorption. The product is not absorbed and impedes the absorption of macronutrients.
- Other mechanisms of action of fiber include altered secretion of gut hormones,  inhibition of digestive enzyme activity.
- It has been implicated in the reduction of low density lipoprotein levels in humans. 
- Minolest is a mixture of psyllium fiber and guar gum, and was administered in a randomized placebo control study. Patients who received Minolest, revealed improvement of overall cholesterol and LDL levels as compared with the placebo group. 
- Another clinical study has indicated that doses of 5.2 g were effective in a clinical cohort of men with type 2 diabetes. The group receiving psyllium fiber showed significant improvement in glucose and lipid values. Furthermore, it was observed that serum LDL levels were 8.9% (P < 0.05) and 13.0% (P < 0.07) lower as compared with the placebo group. 
Examination of current literature would indicate that anywhere between 5 and 10 g of psyllium fiber could be used in a nutritional-based intervention. The FDA guidelines have suggested 1.78 g per serving (four servings daily) for prevention of CVD.  Some contraindications include inhibition of iron absorption, as well as certain minerals including vitamin B12, when used in excess amount. Psyllium reduces adiposity and improves glucose homeostasis in pediatric and adolescent patients suffering from obesity. It also works with the current pharmaceutical Orlistat 1 to limit the number of side effects suffered by patients. 
Momordica Charantia (MC) is found in Southeast Asia, and in sub-tropical areas of South and Central America, respectively. The active agents within MC contain both antiviral and antidiabetic properties.
Mechanism of action
- It decreases islet cell necrosis, repairs damaged cells. It protects functional islets. 
- MC leads to reduction of adiposity and the resultant release of inflammatory factors released by adipocytokines such as TNF-α.
- Hepatic enzymes responsible for the breakdown of lipids such as gluthionine S-transferase are normalized, as a result of Momordica treatment. 
- MC results in increase in cytochrome P-450, which when defective has been implicated with hypertryglyceridemia.  Central obesity tends to also develop in patients with a defective P-450 gene. 
- MC has been implicated in the reduction of adiposity in mice, lowering lipoprotein levels, and as well lowering blood glucose in streptozotocin (STZ) induced rats and human participants as well. ,,
- This vegetable combined with exercise has also been observed to increase insulin sensitivity. 
Clinically effective dosages range between 20 and 50 mg/ kg. , In fact in STZ rats it was observed that MC worked just as effectively as the oral hypoglycemic glibenclamide. Further testing with human participants is required before this supplement can be used to treat insulin resistance. However, the potential of such a herb provides a novel direction of therapeutic usage of nutraceuticals as preventative measures to counter growing rates of obesity.
Resveratrol, a polyphenolic compound found in the skin of grapes and related food products, has been shown to prevent a number of diverse pathologic processes, including CVD, cancer, oxidative stress, and inflammation. 
Mechanism of action
- It enhances the effects of sirtuin SIRT1 in preventing cellular damage associated with aging and chronic illness. 
- It has antiinflammatory and antiadipogenic effects. , Resveratrol has an antiinflammatory effect on TNF-α-induced MCP-1 expression by inhibiting NF-kB transcriptional activity in adipocytes. 
- In animal models, resveratrol repressed toll like receptor 2 (TLR2) and TLR4-mediated proinflammatory signaling cascades in adipose tissue and inhibited NF-kB signaling in the sciatic nerves of rats with STZ induced diabetes. , In human retinal epithelial cells, resveratrol showed an inhibitory effect on hyperglycemia-induced inflammation. 
- It has also shown the potential for preventing CVD by inhibiting inflammatory markers, the cyclooygenase (COX)-1 enzyme, and polyphosphoinositide metabolism in platelets. 
- In rats, resveratrol administration prevented the decrease in vascular NO induced by inflammatory mediators, and it decreased the expression of TNF-α. 
- Vitisin A, a resveratrol tetramer purified from the skin of grape trees, has antiinflammatory, antiadipogenic, and anticholestrolemic activities. ,, Vitisin A reduces the expression of LPS-stimulated proinflammatory markers in macrophages and decreases adipocyte differentiation by inhibiting PPARγ activation. Inhibition of cellular 3-hydroxy-3-methylgluctaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, can lower the levels of circulating cholesterol and several proinflammatory cytokines products of NF-kB target genes.
- In a recent study by Sinclair et al., resveratrol ingestion was associated with reduction in mean systolic blood pressure, leptin levels, systemic markers of inflammation, plasma glucose, and insulin increased energy expenditure. 
- Another study on rats demonstrated fat lowering effects by a reduction in fatty acid uptake from circulating triacylglycerols and also in de novo lipogenesis by reducing the activity of lipogenic enzymes like lipoprotein lipase, acetyl-CoA carboxylase, malic enzyme, glucose-6P-dehydrogenase, acetyl-CoA carboxylase, and fatty acid synthase. 
Resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. 
Flavonoids belong to polyphenol subclass, widely distributed in plants, and in the (diet fruits, vegetables), and certain beverages (including tea, coffee, fruit juices, and wine) and they exhibit a variety of health benefits. The antiinflammatory properties of flavonoids have been extensively studied to establish and characterize their potential utility as therapeutic agents in the treatment of inflammatory diseases. 
Mechanism of action
- Antocyanins are found in red fruits and vegetables have antiinflammatory activity in obese adipose tissues, which is mediated by PPAR-γ dependent mechanisms. 
- Cyanidin 3-glucoside (C3G), a typical anthocyanin, downregulates the expression of RBP-4, which is known to contribute to insulin resistance in adipose tissue of diabetic mice and this improvement is associated with the inhibition of inflammatory mediators and stimulation of AMPK activity in adipocytes. ,
- Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, provides beneficial effects in metabolic syndrome. Long-term EGCG treatment impairs the development of obesity and decreases the expression of inflammatory markers, such as MCP-1, in obese mice, suggesting that EGCG-mediated reductions in mesenteric and retroperitoneal adipose tissue weight may have a beneficial impact on high fat-induced inflammation and the development of metabolic syndrome. 
- Polyphenolic compounds, EGCG  and naringenin  increase GLUT translocation in rat L6 skeletal muscle cells, thereby enhancing glucose uptake.
- In isolated rat adipocytes, the polyphenols catechin-gallate, myricetin, and quercetin, widely present in fruits and vegetables directly interact with GLUT4, reducing glucose transport 
- Phytochemicals such as luteolin, a flavonoid found in olive oil and carrots,  resveratrol  and theaflavins found in black tea  have been found to limit lipid accumulation in human liver HepG2 cells. Rhaponticin from rhubarb reduces plasma nonesterified fatty acid and triglyceride levels in addition to preventing liver steatosis 
- EGCG along with other phytochemicals like mangostin, tocopherol inhibit signaling pathways downstream of LPS-mediated TLR activation, ameliorating proinflammatory gene expression. 
- Phloretin, a flavonoid found in apples and strawberries, was found to increase TAG accumulation with an attendant up-regulation of PPARγ and C/EBPa, concomitantly increases in adiponectin expression and secretion were also found. 
- Nobiletin in citrus fruits enhance 3T3-L1 differentiation; nobiletin activated C/EBPb, which is up-stream of PPARγ and induces its expression. 
- Quercetin found in apple, onion, grapes, citrus fruits, tomato, broccoli, and green leafy vegetables reduce ER stress through the inhibition of the phosphoinositide 3-kinase pathway. 
- In humans, green tea consumption has been inversely correlated with liver damage and with the levels of inflammation markers. 
- Citrus flavonoids in animals decrease plasma lipid levels, improve plasma lipid levels, improve glucose tolerance, and attenuate obesity. They reduce hepatic levels of the mRNA for stearoyl CoA desaturase-1 (SCD-1), leading to repression of hyperlipidemia. 
- Tiliroside enhances fatty acid oxidation via the enhancement adiponectin signaling associated with the activation of both AMP-activated protein kinase and PPAR a and ameliorates obesity-induced metabolic disorders, such as hyperinsulinemia and hyperlipidemia, although it does not suppress body weight gain and visceral fat accumulation in obese-diabetic model mice. 
The two major pungent and structurally similar compounds of ginger, 6-gingerol and 6-shogaol, have potent anti inflammatory activities and can improve diabetes and insulin resistance. ,
Mechanism of action
- Both molecules attenuate the effects on TNF a-induced downregulation of adiponectin expression by different mechanisms in adipocytes; 6-shogaol functions as a potent agonist of PPAR γ.
- 6-shogaol inhibits the TNFa-mediated downregulation of adiponectin expression via PPARγ transactivation. In contrast, 6-gingerol inhibits JNK signaling pathways in TNF-a-stimulated adipocytes without affecting PPAR-γ transactivation. 
- 6-gingerol is also a potent inhibitor of cyclooxygenase 2 (COX-2) expression and acts by blocking the activation of p38 MAPK and NFkB73 along with enhancing adipocyte differentiation. 
- Zingerone, a component of ginger, also suppresses the secretion of MCP-1 from adipose tissue of obese mice and inhibits macrophage inflammatory action such as migration and activation. In animals, the ethanol extract of ginger protects against egg albumin-induced acute inflammation and hypoglycemia in models of diabetes. 
- A Chinese study on rats demonstrated significant weight reduction, possibly attributed to inhibition of intestinal absorption of dietary fat by inhibiting its hydrolysis. 
- The combination of Indian gooseberry and ginger lead to significant reduction in serum total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol, and increase in serum HDL cholesterol levels.  Thus, these studies suggest that ginger has the potential to prevent inflammation and inflammation-linked metabolic dysfunction.
Caralluma fimbriata is an edible cactus, used by tribal Indians to suppress hunger, quench thirst, and enhance endurance. It is a traditional Indian famine food. The key phytochemical ingredients in Caralluma are pregnane glycosides, flavone glycosides, megastigmane glycosides, bitter principles, saponins, and various other flavonoids.  The appetite suppressing action of Caralluma could be attributed to the pregnane glycosides, which are particularly rich in plants belonging to the Asclepiadaceae family
Mechanism of action
- The anorexic effect is elaborated by pregnane glycosides, which amplify signaling of the energy sensing function in the basal hypothalamus. 
- Pregnane glycosides act directly on adipose tissue, by inhibiting adipocyte proliferation and differentiation. 
- Caralluma fimbriata may downregulate ghrelin synthesis in the stomach and subsequently neuropeptide-Y in the hypothalamus, with ultimately the same effect of appetite suppression. 
- One gram Caralluma per day lead to 20% decrease in hunger levels accounting to 8% decrease in energy intake and 3 cm decline in waist circumference.  There was a there was a trend toward a greater decrease in body weight, body mass index, hip circumference, body fat, and energy intake.
- Caralluma fimbriata induced significant and dose-dependent inhibition of food intake, with dose-related prevention of gains in body weight, liver weight, and fat pad mass. Alterations in serum lipid profiles associated with weight gain were similarly inhibited, as were the typical increases in serum leptin levels. It also conferred protection against atherogenesis. 
Calcium rich foods
There is a wide range of calcium rich foods such as margarines and dairy products (milk, yoghurt, cheese). There is increasing evidence that dietary calcium plays a role in body weight regulation. 
Mechanism of action
- Calcium binds fat in the intestine resulting in the formation of insoluble calcium fatty acid soaps and reduces fat absorption. 
- Increase in dietary calcium reduces 1,25-dihydroxy vitamin D concentrations, resulting in down regulation of calcium transfer into adipose and pancreatic cells. Inside adipocytes, a reduction in intracellular levels leads to decreased fatty acid synthase transcription that results in lowering of lipogenesis and increased lipolysis. Reduced intracellular calcium in pancreas decreases insulin output, which results in reduced lipogenesis and enhanced lipolysis in adipocytes. 
- Cross sectional studies have found an inverse relation between milk or calcium consumption and body weight.  However, a meta-analysis has not shown any link between calcium intake and greater weight loss. 
- Diet including three or more daily servings of dairy products resulted in significant reduction in adipose tissue mass in obese humans. 
- Chitosan is a polyglucosamine (the second-most-common dietary fiber, after cellulose). It is produced commercially by deacetylation of chitin, which is the structural element in the exoskeleton of crustaceans (such as crabs and shrimp) and cell walls of fungi. Being a soluble dietary fiber, it increases gastrointestinal lumen viscosity and slows down the emptying of the stomach. Chitosan is relatively insoluble in water, but can be dissolved by dilute acids, which would make it a highly viscous dietary fiber.  Such fibers might inhibit the uptake of dietary lipids by increasing the thickness of the boundary layer of the intestinal lumen, which has been observed in animal experiments.  Having very few acetyl groups, chitosan contains cationic groups. Thus chitosan binds to negatively charged bile acids, which causes mixed micelles to be entrapped or disintegrated in the duodenum and ileum.  This would interrupt bile acid circulation and increased sterol excretion, Due to lack of bile salt, fat will not be digested, thereby reducing fat and cholesterol absorption. Several animal experiments have proved its worth. ,
- Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. It is present in a wide variety of foods including milk, cheese, whole- wheat bread, asparagus, fish, and chicken. Carnitine is the key material for oxidation of fatty acids. Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acetyl CoA to obtain usable energy via the citric acid cycle. It removes excess fat and other fatty acid residues. It reduces fat mass, increases muscle mass, and reduces fatigue. All of these effects may contribute to weight loss.  It has substantial antioxidant action.
- Hydroxycitric acid (HCA) , an extract from the dried fruit rind of Garcinia cambogia, has been reported to cause weight loss in humans without stimulating the central nervous system.  HCA has been demonstrated to reduce food intake in animals, suggesting its role in the treatment of obesity and has been demonstrated to increase the availability of serotonin in isolated rat brain cortex. , HCA is a competitive inhibitor of ATP citrate lyase, an extra-mitochondrial enzyme involved in the initial steps of de novo lipogenesis. Consequently, HCA reduces the transformation of citrate into acetyl coenzyme A, a step necessary for the formation of fatty acids in the liver. In addition, there is increased production of hepatic glycogen in the presence of HCA, which may activate glucoreceptors, leading to a sensation of fullness and reduced appetite. ,
- Niacin-bound chromium (NBC) plays an important role in regulating appetite and energy production. A human study involving African-American women who were administered 600 mg of elemental chromium as NBC in two divided doses, a moderate diet and exercise regimen for 2 months resulted in weight and fat loss and sparing of muscle and body composition with no significant adverse effects.  Grant et al.  reported significant weight loss in young obese women consuming 400 mg of NBC per day for 8 weeks with exercise. This study also demonstrated an improved insulin response to an oral glucose load. In another animal study, rats were fed huge amounts of NBC for over a year and demonstrated no evidence of toxicity. 
- Gymnema sylvestre extract (GSE) helps promote weight loss and controls blood sugar levels.  GSE-derived peptide gurmarin inhibits the sweet taste response in rats.  Preuss et al. demonstrated a significant lowering of cholesterol with GSE ingestion in hypertensive rats that were fed a high sucrose diet, while the placebo group showed a significant increase in cholesterol levels. GSE administered (400 mg/day) to insulin-dependent diabetes mellitus patients for 10-12 months resulted in significant improvement with no adverse side effects.  A human study involving humans, intake of the combination of HCA-SX, NBC, and GSE was demonstrated to be an effective and safe weight-loss formula that can facilitate a reduction in excess body weight and BMI (5-6%), while promoting healthy blood lipid levels. 
| Conclusion|| |
Pathogenic obesity is a complex and dynamic process involving a multitude of steps like metabolic endotoxemia, increased nonesterified fatty acids, hypertrophic adipocytes, increased adipocyte hypoxia culminating in endothelial reticulum stress, and inflammation.  Additionally nutraceuticals with antiinflammatory activities can improve insulin sensitivity. Ideal nutraceuticals should deal with the above pathogenetic steps apart from reducing calorie intake and increasing energy expenditure. Optimizing health with the inclusion of nutraceuticals, will allow for more individuals to be able to control their obesity, and decrease the burden that it may place on them physically, socially, and psychologically. Further research should focus on limiting expansion of adipocytes, inhibition of adipogenesis, and promotion of adipocyte apoptosis.
| Acknowledgements|| |
All the authors would extend their heartfelt thanks to Dr. Jagadeesh Tangudu, M Tech, MS, PhD and Sowmya Jammula, M Tech for their immense and selfless contribution toward manuscript preparation, language editing, and final approval of text.
| References|| |
|1.||World Health Organisation, Obesity and overweight, Fact sheet no. 311. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/index.html. [Last accessed on 2012 Mar 20]. |
|2.||Laing P. Childhood obesity: A public health threat. Paediatr Nurs 2002;14:14-6. |
|3.||Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53. |
|4.||Campfield LA, Brandon P, Smith FJ. On-line continuous measurement of blood glucose and meal pattern in free-feeding rats; the role of glucose in meal initiation. Brain Res Bull 1985;14:605-16. |
|5.||Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immune reactive-leptin concentrations in normal weight and obese humans. N Engl J Med 1996;334:292- 5. |
|6.||Bray GA, York DA. Leptin and clinical medicine: A new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997;82:2771. |
|7.||Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623-30. |
|8.||Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86:5992. |
|9.||Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, et al. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes 2005;29:1130-6. |
|10.||Barrachina MD, Martinez V, Wang L, Wei JY, Tache Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci U S A 1997;94:10455-60. |
|11.||Erlanson-Albertsson C, York D. Enterostatin a peptide regulating fat intake. Obes Res 1997;5:360-72. |
|12.||Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349:941-8. |
|13.||Berthoud HR. Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 2002;26:393-428. |
|14.||Shor Posnar G, Grinker JA, Marinescu C. Hypothalamic serotonin in the control of meal patterns and macronutrient selection. Brain Res Bull 1986;17:663-71. |
|15.||Boosalis MG, Gemayel N, Lee A, Bray GA, Laine L, Cohen H. Cholecystokinin and satiety: Effect of hypothalamic obesity and gastric bubble insertion. Am J Physiol 1992;262:R241-4. |
|16.||Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, et al. Beta-3-adrenergic receptors on white and brown adipocytes mediate beta-3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. J Biol Chem 1997;272:17686-93. |
|17.||Tataranni PA, Young JB, Bogardus C, Ravussin E. A low sympatho adrenal activity is associated with body weight gain and development of central adiposity in Pima Indian men. Obes Res 1997;5:341-7. |
|18.||Trayhurn P, Wood IS. Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347-55. |
|19.||Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-a: Direct role in obesity-linked insulin resistance. Science 1993;259:87-91. |
|20.||Sethi JK, Hotamisligil GS. The role of TNF-a in adipocyte metabolism. Semin Cell Dev Biol 1999;10:19-29. |
|21.||Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801. |
|22.||Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: Modulation by nutrients and inflammation. J Clin Invest 2008;118:2992-3002. |
|23.||Aasheim ET, Hofso D, Hjelmesaeth J, Birkeland KI, Bohmer T. Vitamin status in morbidly obese patients: A cross-sectional study. Am J Clin Nutr 2008;87:362-9. |
|24.||Chrysohoou C, Panagiotakos DB, Pitsavos C, Skoumas I, Papademetriou L, Economou M, et al. The implication of obesity on total antioxidant capacity in apparently healthy men and women: The ATTICA study. Nutr Metab Cardiovasc Dis 2007;17:590-7. |
|25.||Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007;51:301-23. |
|26.||Wolfe S. Potential benefits of functional foods and nutraceuticals to the Agri-Food industry in Canada. Available from: www.agr.gc.ca/misb/fb-ba/nutra/index_e.php?s1=bmi&page=bmi-a. [Last cited in 2002]. |
|27.||Dao HH, Frelut ML, Oberlin F, Peres G, Bourgeois P, Navarro J. Effects of a multidisciplinary weight loss intervention on body composition in obese adolescents. Int J Obes Relat Metab Disord 2004;28:290-9. |
|28.||Woo HM, Kang JH, Kawada T, Yoo H, Sung MK, Yu R. Active spice-derived components can inhibit inflammatory responses of adipose tissue in obesity by suppressing inflammatory actions of macrophages and release of monocyte chemoattractant protein-1 from adipocytes. Life Sci 2007;80:926-31. |
|29.||Wang SL, Li Y, Wen Y, Chen YF, Na LX, Li ST, et al. Curcumin, a potential inhibitor of upregulation of TNF-a and IL-6 induced by palmitate in 3T3- L1 adipocytes through NF-kB and JNK pathway. Biomed Environ Sci 2009;22:32-9. |
|30.||Pendurthi UR, Rao LV. Suppression of transcription factor Egr-1 by curcumin. Thromb Res 2000;97:179-89. |
|31.||Pal R, Cristan EA, Schnittker K, Narayan M. Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention: Implications for subcellular traffic and neurodegenerative disorders. Biochem Biophys Res Commun 2010;392:567-71. |
|32.||Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology 2008;149:3549-58. |
|33.||Jain SK, Rains J, Croad J, Larson B, Jones K. Curcumin supplementation lowers TNF-a, IL-6, IL-8, and MCP-1 secretion in high glucose treated cultured monocytes and blood levels of TNF-a,IL- 6,MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid Redox Signal 2009;11:241-9. |
|34.||Ejaz A, Wu D, Kwan P, Meydani M. Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. J Nutr 2009;139:919-25. |
|35.||Joo JI, Kim DH, Choi JW, Yun JW. Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. J Proteome Res 2010;9:2977-87. |
|36.||Kim DH, Joo JI, Choi JW, Yun JW. Differential expression of skeletal muscle proteins in high-fat diet-fed rats in response to capsaicin feeding. Proteomics 2010;10:2870-81. |
|37.||Masuda Y, Haramizu S, Oki K, Ohnuki K, Watanabe T, Yazawa S, et al. Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol 2003;95:2408-15. |
|38.||Yoshioka M, Doucet E, Drapeau V, Dionne I, Tremblay A. Combined effects of red pepper and caffeine consumption on 24 h energy balance in subjects given free access to foods. Br J Nutr 2001;85:203-11. |
|39.||Shin KO, Moritani T. Alterations of autonomic nervous activity and energy metabolism by capsaicin ingestion during aerobic exercise in healthy men. J Nutr Sci Vitaminol (Tokyo) 2007;53:124- 32. |
|40.||Kim CS, Kawada T, Kim BS, Han IS, Choe SY, Kurata T, et al. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal 2003;15:299-306. |
|41.||Manjunatha H, Srinivasan K. Protective effect of dietary curcumin and capsaicin on induced oxidation of low-density lipoprotein, iron-induced hepatotoxicity and carrageenan-induced inflammation in experimental rats. FEBS J 2006;273:4528-37. |
|42.||Park JY, Kawada T, Han IS, Kim BS, Goto T, Takahashi N, et al. Capsaicin inhibits the production of tumor necrosis factor by LPS-stimulated murine macrophages, RAW 264.7: A PPARγ ligand-like action as a novel mechanism. FEBS Lett 2004;572:266-70. |
|43.||Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, et al. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res 2007;100:1063-70. |
|44.||Chan DC, Watts GF, Mori TA, Barrett PH, Redgrave TG, Beilin LJ. Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 2003;77:300-7. |
|45.||Azain MJ. Role of fatty acids in adipocyte growth and development. J Anim Sci 2004;82:916-24. |
|46.||Dauchy RT, Blask DE, Sauer LA, Davidson LK, Krause JA, Smith LC, et al. Physiologic melatonin concentration, omega-3 fatty acids, and conjugated linoleic acid inhibit fatty acid transport in rodent hind limb skeletal muscle in vivo. Comp Med 2003;53:186- 90. |
|47.||Blankson H, Stakkestad JA, Fagertun H, Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr 2000;130:2943-8. |
|48.||Lavigne C, Tremblay F, Asselin G, Jacques H, Marette A. Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats. Am J Physiol Endocrinol Metab 2001;281:E62-71. |
|49.||Dyck DJ. Dietary fat intake, supplements, and weight loss. Can J Appl Physiol 2000;25:495-523. |
|50.||Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015-25. |
|51.||Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, et al. Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr 2009;139:1495-501. |
|52.||Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. GPR120 is an w-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010;142:687- 98. |
|53.||Todoric J, Löffler M, Huber J, Bilban M, Reimers M, Kadl A, et al. Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n-3 polyunsaturated fatty acids. Diabetologia 2006;49:2109-19. |
|54.||Meijerink J, Plastina P, Vincken JP, Poland M, Attya M, Balvers M, et al. The ethanolamide metabolite of DHA, docosahexaenoylethanolamine, shows immunomodulating effects in mouse peritoneal and RAW264.7 macrophages: Evidence for a new link between fish oil and inflammation. Br J Nutr 2011;4:1-10. |
|55.||Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nakakuki M, Nagai R, et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology 2003;38:1529- 39. |
|56.||Robinson LE, Buchholz AC, Mazurak VC. Inflammation, obesity, and fatty acid metabolism: Influence of n-3 polyunsaturated fatty acids on factors contributing to metabolic syndrome. Appl Physiol Nutr Metab 2007;32:1008-24. |
|57.||Bergmann JF, Chassany O, Petit A, Triki R, Caulin C, Segrestaa JM. Correlation between echographic gastric emptying and appetite: Influence of psyllium. Gut 1992;33:1042-3. |
|58.||Slavin JL. Dietary fiber and body weight. Nutrition 2005;21:411-8. |
|59.||Kris-Etherton PM, Taylor DS, Smiciklas-Wright H, Mitchell DC, Bekhuis TC, Olson BH, et al. High-soluble-fiber foods in conjunction with a telephone-based, personalized behavior change support service result in favorable changes in lipids and lifestyles after 7 weeks. J Am Diet Assoc 2002;102:503-10. |
|60.||Tai ES, Fok AC, Chu R, Tan CE. A study to assess the effect of dietary supplementation with soluble fibre (Minolest) on lipid levels in normal subjects with hypercholesterolaemia. Ann Acad Med Singapore 1999;28:209-13. |
|61.||Anderson JW, Baird P, Davis RH Jr, Ferreri S, Knudtson M, Koraym A, et al. Health benefits of dietary fiber. Nutr Rev 2009;67:188-205. |
|62.||Jenkins DJ, Kendall CW, Vuksan V, Vidgen E, Parker T, Faulkner D. et al. Soluble fiber intake at a dose approved by the US Food and Drug Administration for a claim of health benefits: Serum lipid risk factors for cardiovascular disease assessed in a randomized controlled crossover trial. Am J Clin Nutr 2002;75:834-9. |
|63.||Cavaliere H, Floriano I, Medeiros-Neto G. Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid). Int J Obes Relat Metab Disord 2001;25:1095-9. |
|64.||Ahmed I, Adeghate E, Sharma AK, Pallot DJ, Singh J. Effects of Momordica charantia fruit juice on islet morphology in the pancreas of the streptozotocin-diabetic rat. Diabetes Res Clin Pract 1998;40:145-51. |
|65.||Tennekoon KH, Jeevathayaparan S, Angunawala P, Karunanayake EH, Jayasinghe KS. Effect of Momordica charantia on key hepatic enzymes. J Ethnopharmacol 1994;44:93-7. |
|66.||Irizar A, Barnett CR, Flatt PR, Ioannides C. Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat. Eur J Pharmacol 1995;293:385-93. |
|67.||Baghaei F, Rosmond R, Westberg L, Hellstrand M, Eriksson E, Holm G, et al. The CYP19 gene and associations with androgens and abdominal obesity in premenopausal women. Obes Res 2003;11:578-85. |
|68.||Tian WX, Li LC, Wu XD, Chen CC. Weight reduction by Chinese medicinal herbs may be related to inhibition of fatty acid synthase. Life Sci 2000;74:2389-99. |
|69.||Senanayake GV, Maruyama M, Shibuya K, Sakono M, Fukuda N, Morishita T, et al. The effects of bitter melon (Momordica charantia) on serum and liver triglyceride levels in rats. J Ethnopharmacol 2004;91:257-62. |
|70.||Leatherdale BA, Panesar RK, Singh G, Atkins TW, Bailey CJ, Bignell AH. Improvement in glucose tolerance due to Momordica charantia (karela). Br Med J (Clin Res Ed) 1981;282:1823-4. |
|71.||Miura T, Itoh Y, Iwamoto N, Kato M, Ishida T. Suppressive activity of the fruit of Momordica charantia with exercise on blood glucose in type 2 diabetic mice. Biol Pharm Bull 2004;27:248-50. |
|72.||Virdi J, Sivakami S, Shahani S, Suthar AC, Banavalikar MM, Biyani MK. Antihyperglycemic effects of three extracts from Momordica charantia. J Ethnopharmacol 2003;88:107-11. |
|73.||Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986;17:277-82. |
|74.||Baur JA, Sinclair DA. Therapeutic potential of resveratrol: The in vivo evidence. Nat Rev Drug Discov 2006;5:493-506. |
|75.||Pillarisetti S. A review of Sirt1 and Sirt1 modulators in cardiovascular and metabolic diseases. Recent Pat Cardiovasc Drug Discov 2008;3:156-64. |
|76.||Kim S, Jin Y, Choi Y, Park T. Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes inmice. Biochem Pharmacol 2011;81:1343-51. |
|77.||Zhu J, Yong W, Wu X, Yu Y, Lv J, Liu C, et al. Anti-inflammatory effect of resveratrol on TNF-a-induced MCP-1 expression in adipocytes. Biochem Biophys Res Commun 2008;369:471-7. |
|78.||Kumar A, Sharma SS. NF-kB inhibitory action of resveratrol: A probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun 2010;394:360-5. |
|79.||Losso JN, Truax RE, Richard G. Trans-resveratrol inhibits hyperglycemia-induced inflammation and connexin downregulation in retinal pigment epithelial cells. J Agric Food Chem 2010;58:8246-52. |
|80.||Szewczuk LM, Forti L, Stivala LA, Penning TM. Resveratrol is a peroxidase mediated inactivator of COX-1 but not COX-2: A mechanistic approach to the design of COX-1 selective agents. J Biol Chem 2004;279:22727-37. |
|81.||Zhang H, Zhang J, Ungvari Z, Zhang C. Resveratrol improves endothelial function: Role of TNF-a and vascular oxidative stress. Arterioscler Thromb Vasc Biol 2009;29:1164-71. |
|82.||Mi Jeong S, Davaatseren M, Kim W, Park SK, Kim SH, Hur HJ, et al. Vitisin A suppresses LPS-induced NO production by inhibiting ERK, p38, and NF-kB activation in RAW 264.7 cells. Int Immunopharmacol 2009;9:319-23. |
|83.||Kim SH, Park HS, Lee MS, Cho YJ, Kim YS, Hwang JT, et al. Vitisin A inhibits adipocyte differentiation through cell cycle arrest in 3T3-L1 cells. Biochem Biophys Res Commun 2008;372:108-13. |
|84.||Koo M, Kim SH, Lee N, Yoo MY, Ryu SY, Kwon DY, et al. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitory effect of Vitis vinifera. Fitoterapia 2008;79:204-6. |
|85.||Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011;14:612-22. |
|86.||Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Arias N, Andres-Lacueva C, et al. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab (Lond) 2011;8:29. |
|87.||Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci 2011;1215:161-9. |
|88.||Garcia-Lafuente A, Guillamón E, Villares A, Rostagno MA, Martínez JA. Flavonoids as antiinflammatory agents: Implications in cancer and cardiovascular disease. Inflamm Res 2009;58:537- 52. |
|89.||Tsuda T. Regulation of adipocyte function by anthocyanins: Possibility of preventing the metabolic syndrome. J Agric Food Chem 2008;56:642-6. |
|90.||Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol 2007;74:1619- 27. |
|91.||Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS. The major green tea polyphenol, (-) - epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 2008;138:1677-83. |
|92.||Zhang ZF, Li Q, Liang J, Dai XQ, Ding Y, Wang JB, et al. Epigallocatechin-3-O- gallate (EGCG) protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition. Phytomedicine 2010;17:14-8. |
|93.||Zygmunt K, Faubert B, MacNeil J, Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 2010;398:178-83. |
|94.||Strobel P, Allard C, Perez-Acle T, Calderon R, Aldunate R, Leighton F. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochem J 2005;386:471-8. |
|95.||Liu JF, Ma Y, Wang Y, Du ZY, Shen JK, Peng HL. Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress. Phytother Res 2011;25:588-96. |
|96.||Lin CL, Huang HC, Lin JK. Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells. J Lipid Res 2007;48:2334-43. |
|97.||Chen J, Ma M, Lu Y, Wang L, Wu C, Duan H. Rhaponticin from rhubarb rhizomes alleviates liver steatosis and improves blood glucose and lipid profiles in KK/Ay diabetic mice. Planta Med 2009;75:472-7. |
|98.||Hong Byun E, Fujimura Y, Yamada K, Tachibana H. TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. J Immunol 2010;185:33-45. |
|99.||Hassan M, Yazidi CE, Landrier JF, Lairon D, Margotat A, Amiot MJ. Phloretin enhances adipocyte differentiation and adiponectin expression in 3T3-L1 cells. Biochem Biophys Res Commun 2007;361:208-13. |
|100.||Saito T, Abe D, Sekiya K. Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. Biochem Biophys Res Commun 2007;357:371-6. |
|101.||Natsume Y, Ito S, Satsu H, Shimizu M. Protective effect of quercetin on ER stress caused by calcium dynamics dysregulation in intestinal epithelial cells. Toxicology 2009;258:164-75. |
|102.||Steptoe A, Gibson EL, Vuononvirta R, Hamer M, Wardle J, Rycroft JA, et al. The effects of chronic tea intake on platelet activation and inflammation: A double-blind placebo controlled trial. Atherosclerosis 2007;193:277-82. |
|103.||Nichols LA, Jackson DE, Manthey JA, Shukla SD, Holland LJ. Citrus flavonoids repress the mRNA for stearoyl-CoA desaturase, a key enzyme in lipid synthesis and obesity control, in rat primary hepatocytes. Lipids Health Dis 2011;10:36. |
|104.||Goto T, Teraminami A, Lee JY, Ohyama K, Funakoshi K, Kim YI, et al. Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice. J Nutr Biochem 2012;23:768-76. |
|105.||Ojewole JA. Analgesic, antiinflammatory and hypoglycaemic effects of ethanol extract of Zingiber officinale (Roscoe) rhizomes (Zingiberaceae) in mice and rats. Phytother Res 2006;20:764-72. |
|106.||Sekiya K, Ohtani A, Kusano S. Enhancement of insulin sensitivity in adipocytes by ginger. Biofactors 2004;22:153-6. |
|107.||Isa Y, Miyakawa Y, Yanagisawa M, Goto T, Kang MS, Kawada T, et al. 6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF- mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2008;373:429-34. |
|108.||Han LK, Gong XJ, Kawano S, Saito M, Kimura Y, Okuda H. Antiobesity actions of Zingiber officinale Roscoe. Yakugaku Zasshi 2005;125:213-7. |
|109.||Kamal R, Aleem S. Clinical evaluation of the efficacy of a combination of Zanjabeel (Zingiber Officianale) and amla (Emblica officianalis) in hyperlipidemia. Indian J Tradit Knowl 2009;8:413-6. |
|110.||Bader A, Braca A, De Tommasi N, Morelli I. Further constituents from Caralluma negevensis. Phytochemistry 2003;62:1277-81. |
|111.||MacLean DB, Luo LG. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: Studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res 2004;1020:1-11. |
|112.||Cioffi G, Sanogo R, Vassallo A, Dal Piaz F, Autore G, Marzocco S, et al. Pregnane glycosides from Leptadenia pyrotechnica. J Nat Prod 2006;69:625-35. |
|113.||Gardiner JV, Kong WM, Ward H, Murphy KG, Dhillo WS, Bloom SR. AAV mediated expression of antisense neuropeptide Y cRNA in the arcuate nucleus of rats results in decreased weight gain and food intake. Biochem Biophys Res Commun 2005;327:1088-93. |
|114.||Kuriyan R, Raj T, Srinivas SK, Vaz M, Rajendran R, Kurpad AV. Effect of Caralluma fimbriata extract on appetite, food intake and anthropometry in adult Indian men and women. Appetite 2007;48:338-44. |
|115.||Kamalakkannan S, Rajendran R, Venkatesh RV, Clayton P, Akbarsha MA. Antiobesogenic and Antiatherosclerotic Properties of Caralluma fimbriata Extract. J Nutr Metab 2010;2010:285301. |
|116.||Zemel MB, Miller SL. Dietary calcium and dairy modulation of adiposity and obesity risk. Nutr Rev 2004;62:125-31. |
|117.||Welberg JW, Monkelbaan JF, de Vries EG, Muskiet FA, Cats A, Oremus ET, et al. Effects of supplemental dietary calcium on quantitative and qualitative fecal fat excretion in man. Ann Nutr Metab 1994;38:185-91. |
|118.||Jacqmain M, Doucet E, Després JP, Bouchard C, Tremblay A. Calcium intake, body composition, and lipoprotein-lipid concentrations in adults. Am J Clin Nutr 2003;77:1448-52. |
|119.||Barr SI. Increased dairy product or calcium intake: Is body weight or composition affected in humans? J Nutr 2003;133:245S-8S. |
|120.||Furda I. Interaction of dietary fiber with lipids-mechanistic theories and their limitations. Adv Exp Med Biol 1990;270:67-82. |
|121.||Ikeda I, Sugano M, Yoshida K, Sasaki E, Iwamoto Y, Hatano K. Effects of chitosan hydrolyzates on lipid absorption and on serum and liver lipid concentration in rats. Agric Food Chem 1993;41:431-5. |
|122.||Cha YS. Effects of l-carnitine on obesity, diabetes, and as an ergogenic aid. Asia Pac J Clin Nutr 2008;17 Suppl 1:306-8. |
|123.||Clouatre D, Rosenbaum M. The Diet and Health Benefits of HCA. New Canaan, CT: A Keats Good Health Guide; 1994. p. 9. |
|124.||Lowenstein JM. Effect of (-)-hydroxycitrate on fatty acid synthesis by rat liver in vivo. J Biol Chem 1971;246:629-32. |
|125.||Triscari J, Sullivan AC. Anti-obesity activity of a novel lipid synthesis inhibitor. Int J Obes 1984;8:227-39. |
|126.||Crawford V, Scheckenbach R, Preuss HG. Effects of niacin-bound chromium supplementation on body composition in overweight African-American women. Diabetes Obes Metab 1999;1:331-7. |
|127.||Grant KE, Chandler RM, Castle AL, Ivy JL. Chromium and exercise training: Effect on obese women. Med Sci Sports Exerc 1997;29:992-8. |
|128.||Preuss HG, Montamarry S, Echard B, Scheckenbach R, Bagchi D. Long term effects of chromium, grape seed extract, and zinc on variousmetabolic parameters in rats. Mol Cell Biochem 2001;223:95-102. |
|129.||Prakash AO, Mathur S, Mathur R. Effect of feeding Gymnema sylvestre leaves on blood glucose in beryllium nitrate treated rats. J Ethnopharmacol 1986;18:143-6. |
|130.||Preuss HG, Jarrell ST, Scheckenbach R, Lieberman S, Anderson RA. Comparative effects of chromium, vanadium and Gymnema sylvestre on sugar-induced blood pressure elevations in SHR. J Am Coll Nutr 1998;17:116-23. |
|131.||Preuss HG, Bagchi D, Bagchi M, Rao CV, Dey DK, Satyanarayana S. Effects of a natural extract of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss. Diabetes Obes Metab 2004;6:171-80. |
|132.||Conroy KP, Davidson IM, Warnock M. Pathogenic obesity and nutraceuticals. Proc Nutr Soc 2011;70:426-38. |
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