Journal of Medical Nutrition and Nutraceuticals

REVIEW ARTICLE
Year
: 2012  |  Volume : 1  |  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

Correspondence Address:
Sunil K Kota
Resident in Endocrinology, Department of Endocrinology, Medwin Hospitals, Chiragh Ali Lane, Nampally, Hyderabad - 500001, Andhra Pradesh
India

Abstract

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.



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 Jul 23 ];1:63-76
Available from: http://www.jmnn.org/text.asp?2012/1/2/63/101288


Full Text

 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. [1] 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. [1] 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. [2],[3]

 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.{Figure 1}

Afferent signals

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 [4] initiates a sensation of satiety whereas a fall in glucose promotes hunger. This effect is itself mediated by different neurotransmitters, hormones, and peptides. Leptin [5] 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. [6] 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. [7],[8],[9] 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. [10],[11],[12] 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}

Central processing unit

Afferent impulses proceed centrally to the hindbrain and the hypothalamus for integration and processing. [13] 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}

Serotonin (5-HT) acts via postsynaptic 5- HT 1B receptors on para ventricular nucleus (PVN) of hypothalamus to reduce food intake. [14] 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. [15]

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.

Efferent mediators

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. [16] 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. [17] 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. [18] 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). [19],[20],[21] 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. [22] Furthermore, plasma levels of vitamins and antioxidants are lower in the obese [23] and an inverse relationship has been shown between serum total antioxidant capacity and waist circumference. [24] Research also indicates the modulatory effects of vitamins and antioxidants on the immune system [25] 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. [26] 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. [27] The current article reviews the nutraceutical agents for obesity treatment. [Table 1] gives an overview of common antiobesity nutraceutical plant preparations in India.{Table 1}

Curcumin

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. [28],[29] 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. [30] 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. [31] 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.

Evidence



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. [32] 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. [33] 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. [34]

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:



Standardized curcumin powder: 400 to 600 mg three times dailyTincture (1:2): 15 to 30 drops up to four times dailyLiquid extracts (1:1): 30 to 90 drops daily

Caspaicin

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. [35],[36] 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. [37] Upregulation of uncoupling protein 1 (UCP 1) in adipose tissue further contributes to thermogenesis.It has appetite regulator activity. [38] 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). [39]

Evidence



Several studies have shown potential benefits of capsaicin for treating obesity and insulin resistance in animal models and clinical studies [40],[41] Capsaicin was shown in animal studies to increase the insulin-stimulated uptake of glucose in muscle cells [42] Zhu et al. have demonstrated that activation of transient receptor potential vanilloid type-1 (TRPV1) by capsaicin prevents adipogenesis. [43]

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. [45] 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. [46] 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.

Evidence



Supplementation of CLA reduced fat mass of obese individuals. [47] 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. [47] 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. [48]

However, what may be problematic is that there have been few clinical evaluations on humans. [49] 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. [50] However, ω-3 polyunsaturated fatty acids (PUFAs) from fish oils, such as docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA), are known antiinflammatory factors. [51] 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. [52] 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. [53] Docohexaenoylethanolamine (DHEA), the ethnaolamide metabolite of DHA, modulates inflammation by reducing MCP-1 and nitric oxide (NO) production in macrophages. [54]

Evidence



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. [55] 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. [56]

In conclusion, fish oil supplements can alleviate metabolic disease by modulating inflammatory signaling pathways.

Psyllium fiber

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. [57] 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, [58] inhibition of digestive enzyme activity.

Evidence



It has been implicated in the reduction of low density lipoprotein levels in humans. [59] 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. [60] 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. [61]

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. [62] 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. [63]

Momordica charantia

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. [64] 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. [65] MC results in increase in cytochrome P-450, which when defective has been implicated with hypertryglyceridemia. [66] Central obesity tends to also develop in patients with a defective P-450 gene. [67]

Evidence



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. [68],[69],[70] This vegetable combined with exercise has also been observed to increase insulin sensitivity. [71]

Clinically effective dosages range between 20 and 50 mg/ kg. [72],[73] 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

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. [74]

Mechanism of action



It enhances the effects of sirtuin SIRT1 in preventing cellular damage associated with aging and chronic illness. [75] It has antiinflammatory and antiadipogenic effects. [76],[77] Resveratrol has an antiinflammatory effect on TNF-α-induced MCP-1 expression by inhibiting NF-kB transcriptional activity in adipocytes. [77] 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. [76],[78] In human retinal epithelial cells, resveratrol showed an inhibitory effect on hyperglycemia-induced inflammation. [79] It has also shown the potential for preventing CVD by inhibiting inflammatory markers, the cyclooygenase (COX)-1 enzyme, and polyphosphoinositide metabolism in platelets. [80] In rats, resveratrol administration prevented the decrease in vascular NO induced by inflammatory mediators, and it decreased the expression of TNF-α. [81] Vitisin A, a resveratrol tetramer purified from the skin of grape trees, has antiinflammatory, antiadipogenic, and anticholestrolemic activities. [82],[83],[84] 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.

Evidence



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. [85] 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. [86]

Resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. [87]

Flavonoids

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. [88]

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. [89] 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. [89],[90] 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. [91] Polyphenolic compounds, EGCG [92] and naringenin [93] 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 [94] Phytochemicals such as luteolin, a flavonoid found in olive oil and carrots, [95] resveratrol [95] and theaflavins found in black tea [96] 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 [97] EGCG along with other phytochemicals like mangostin, tocopherol inhibit signaling pathways downstream of LPS-mediated TLR activation, ameliorating proinflammatory gene expression. [98] 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. [99] Nobiletin in citrus fruits enhance 3T3-L1 differentiation; nobiletin activated C/EBPb, which is up-stream of PPARγ and induces its expression. [100] 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. [101]

Evidence



In humans, green tea consumption has been inversely correlated with liver damage and with the levels of inflammation markers. [102] 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. [103] 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. [104]

Ginger components

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. [105],[106]

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. [107] 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. [106] 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. [105]

Evidence



A Chinese study on rats demonstrated significant weight reduction, possibly attributed to inhibition of intestinal absorption of dietary fat by inhibiting its hydrolysis. [108] 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. [109] Thus, these studies suggest that ginger has the potential to prevent inflammation and inflammation-linked metabolic dysfunction.

Caralluma fimbriata

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. [110] 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. [111] Pregnane glycosides act directly on adipose tissue, by inhibiting adipocyte proliferation and differentiation. [112] Caralluma fimbriata may downregulate ghrelin synthesis in the stomach and subsequently neuropeptide-Y in the hypothalamus, with ultimately the same effect of appetite suppression. [113]

Evidence



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. [114] 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. [115]

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. [116]

Mechanism of action



Calcium binds fat in the intestine resulting in the formation of insoluble calcium fatty acid soaps and reduces fat absorption. [117] 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. [116]

Evidence



Cross sectional studies have found an inverse relation between milk or calcium consumption and body weight. [118] However, a meta-analysis has not shown any link between calcium intake and greater weight loss. [119] Diet including three or more daily servings of dairy products resulted in significant reduction in adipose tissue mass in obese humans. [116]

Others



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. [120] 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. [121] 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. [120] 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. [120],[121] 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. [122] 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. [123] 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. [124],[125] 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. [124],[125] 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. [126] Grant et al. [127] 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. [128] Gymnema sylvestre extract (GSE) helps promote weight loss and controls blood sugar levels. [129] GSE-derived peptide gurmarin inhibits the sweet taste response in rats. [129] 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. [130] 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. [131]

 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. [132] 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.

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