Dietary phytochemicals and their potential effects on obesity: A review

Pharmacological Research 64 (2011) 438–455

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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Dietary phytochemicals and their potential effects on obesity: A review Marta González-Castejón, Arantxa Rodriguez-Casado ∗ IMDEA Food Institute, CLAID-PCM Building C/Faraday 7, Campus de Cantoblanco, Madrid 28049, Spain

a r t i c l e

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Article history: Received 11 July 2011 Accepted 11 July 2011 Keywords: Obesity Adipocytes Phytochemical Food Gene–nutrient interaction Multigenic diseases Nutritional prevention Anti-obesity

a b s t r a c t The incidence of obesity is rising at an alarming rate and is becoming a major public health concern with incalculable social costs. Indeed, obesity facilitates the development of metabolic disorders such as diabetes, hypertension, and cardiovascular diseases in addition to chronic diseases such as stroke, osteoarthritis, sleep apnea, some cancers, and inflammation-bases pathologies. In this review we summarize the progresses made in our understanding of obesity, including the role of inflammation process, the recently understood endocrine function of adipose tissue, as well as passive roles of processes of energy storage and adipogenesis related to fat cell lifecycle: differentiation, maturation, and apoptosis. In addition, the article discusses the anti-obesity potential of dietary phytochemicals and analyzes their mechanisms of action, e.g. induction of apoptosis and lipolysis and inhibition of inflammation. © 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to assess obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Causes of obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Inflammatory components of obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Neurological components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathologies associated with obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Dislipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Cardiac alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. The metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Terpenoids (isoprenoids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Organosulfurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +34 91 279 6987; fax: +34 91 188 0756. E-mail address: [email protected] (A. Rodriguez-Casado). 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.07.004

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1. Introduction In 1997, the World Health Organization (WHO) announced that obesity had reached epidemic proportions worldwide [1]. This statement is based on the collection and analysis of body mass index (BMI, kg/m2 ) data. Since then, obesity incidence has further arisen at an alarming rate and is becoming a major public health concern with incalculable social costs [2]. Indeed, obesity facilitates the development of metabolic disorders such as diabetes, hypertension, and cardiovascular diseases in addition to chronic diseases such as stroke, osteoarthritis, sleep apnea, some cancers, and inflammation-bases pathologies [3–8]. The strong association between obesity and chronic diseases suggests that the obese are likely to make disproportionate use of health care, leading to a substantially larger expenditure relative to that of normal weight individuals [9]. According to studies from a variety of countries, an obese person incurs in health care expenditures at least 25% higher than those of a healthy person [9]. When production losses are added to health care costs, obesity accounts for a considerable percentage of gross domestic product in most countries (>1% in US, >3.6% in China) [10]. Obesity is defined as a phenotypic manifestation of abnormal or excessive fat accumulation that alters health and increases mortality. The most common obesity classification is based on BMI intervals related to risk of mortality [1,11]. In brief, obesity is classified as class I for a BMI between 30 and 34.9 associated with a moderate risk, class II for a BMI between 35 and 39.9 with a high risk, and class III for a BMI 40 or above associated with a very high risk of mortality (Fig. 1). In terms of anatomy, we usually refer to the distribution of body fat deposition. The ratio of waist-to-hip circumferences (WHR) measures the degree of central (visceral, abdominal) vs. peripheral (subcutaneous) adiposity. Visceral fat is a major risk for metabolic disorders, whereas peripheral fat appears to be benign to metabolic complications [12]. In terms of etiology, obesity is classified as primary or secondary. Obesity can be iatrogenic, i.e. secondary to drug treatments (antipsychotic, antidepressant, antiepileptic, steroids, insulin), or to certain diseases (Cushing syndrome, hypothyroidism, hypothalamic defects) [12]. Otherwise, obesity as a primary disorder follows a positive energy balance. The identification of the primary causes of this imbalance remains challenging and comprises the majority of cases usually diagnosed after causes for secondary obesity are ruled out [13]. As reviewed later, this chronic disease results from complex interactions of genetic, behavioral, and environmental factors correlating with economic and social status and lifestyles [14]. In fact, obesity is more frequent in populations living in environments characterized by long-term energy positive imbalance due to sedentary lifestyle, low resting metabolic rate, or both [15]. Causes of obesity involve genes, metabolism, diet, physical activity, and the socio-cultural environment that characterizes 21st century living [16,17]. Identification of potential molecular targets susceptible to be manipulated from external factor, particularly food and drug agents, may assist people in gaining control over appetite allowing obesity prevention. Nutritional genomics could determine which specific nutrients bring phenotypic changes that influence the obesity risk and could establish which interactions are the most important ones [17,18]. Therefore, specific variants associated with high-risk groups for obesity could be identified by genomic approaches, with the possibility to establish a personalized diet to prevent or delay the disease in taking specific nutrients. Global strategies are focused on dietary and lifestyle modifications, i.e. restrict caloric intake and increase physical activity to slow obesity development [19]. A food field research that has recently aroused considerable interest is the potential of natural products to counteract obesity [20–22]. These products contain

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dietary phytochemical with high potential for health promotion and disease prevention [23–25]. Multiple-phytochemicals combinations may result in synergistic activity that increases their bioavailability and their action on multiple molecular targets, thus offering advantages over treatments with single chemicals [22,26]. The anti-obesity effects of these compounds are mediated by regulation of various pathways, including lipid absorption, intake and expenditure of energy, increasing lipolysis, and decrease lipogenesis, and differentiation and proliferation of preadipocytes [22]. In this review we summarize the progresses made in our understanding of obesity, including the role of inflammation process, the recently understood endocrine function of adipose tissue, as well as passive roles of processes of energy storage and adipogenesis related to fat cell lifecycle: differentiation, maturation, and apoptosis. In addition, the article discusses the anti-obesity potential of dietary phytochemicals and analyzes their mechanisms of action, e.g. induction of apoptosis and lipolysis and inhibition of inflammation. 2. How to assess obesity The procedures for quali-quantitatively measuring body fat range from simple anthropometric methods to imaging and computed technology, capable of directly measure various body tissues in vivo. These methods are useful for diagnosis and precise tracking of obese individuals, in terms of quantity and fat mass distribution [27]. The anthropometric methods assess human body proportions i.e. weight, height, skin folds, circumferences and diameters measurements. The WHO defines overweight as a BMI of 25 to 29.9, and obesity as BMI of 30 in adults, but there is evidence that the risk of chronic diseases in populations increases progressively from a BMI of 21. BMI is the most practical indicator of obesity severity and fat-distribution measures are more likely to be complements than substitutes [28]. National Health and Research Council (NHMRC) reports warned against using BMI for individual cases, as it varies based on age, sex, racial, and ethnic group [29]. The Bioelectrical Impedance Analyzer (BIA) is a noninvasive method for calculating total body water, fat-free, and fat-tissue masses based on the principle that the conductivity of body water varies in different compartments. BIA measures the impedance offered by body tissues in response to the passage of an electric current [27]. In the last years, Dual Energy X-ray Absorptiometry (DEXA) has been used to determinate body fat composition (fat mass, fat-free mass, bone mineral density) in vivo, demonstrating to be accurate and safe. Imaging techniques are considered as the most accurate tools for quantification in vivo of adipose tissue and can be used for measuring fat and skeletal muscle [27]. Nuclear Magnetic Resonance Imaging (NMRI) measures muscle mass, visceral, subcutaneous, liver, pancreas and kidneys fat [27]. Computed Tomography (CT) is another noninvasive imaging technique that requires the body to be irradiated in their entirety [27]. Both imaging methods allow quantifying the size, area, volume and mass of different tissues with acceptable level of accuracy. However, these techniques require expensive equipment and the tests costs remains an obstacle to their routine use. 3. Prevalence The proportion of obese people varies among countries and depends upon environmental and behavioral changes brought about by economic development, modernization, and urbanization. The variation in prevalence of obesity epidemic among various races and communities may be attributed to heredity, age, sex, diet, eating patterns, life style, and/or behavior [30]. As an example, obesity has risen to the top of the public health concern in all indus-

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Fig. 1. BMI classification and cut-off point. The international classification of adult overweight and obesity according to BMI.

trialized countries. The latest (2007) available data collected by the Organization for Economic Co-operation and Development (OECD) on obesity and overweight rates show that over half of the adult population is overweight in at least 13 member countries, including Australia, Spain, the United Kingdom, and the United States [31]. In non-OECD countries such as Brazil, China, and South Africa among others, rates are still somewhat lower than in OECD countries, but increasing at similarly rates [32]. Otherwise, obesity rate is much lower in Japan and Korea and in some European countries such as France and Switzerland, whereas obesity has taken over as the predominant features of malnutrition in South Africa [33]. Globally, there are more than 300 million adults who are obese; an additional major concern is that 42 million children are overweight [34], which makes it one of the major current public health concerns. Gender differences in the prevalence of obesity suggest that there are different metabolic pathways through which obesity develops [35,36]. Different explanations have been proposed to explain the higher prevalence of obesity in women in many countries [37]. One example is that of malnutrition during childhood, which is linked to obesity in adulthood. Evidence demonstrates that women suffering nutritional deprivation during childhood tend to be obese when adult, while this effect does not appear in men [37]. Also, there is evidence of mother-to-child transmission of obesity [38]. Women belonging to disadvantaged socio-economic groups are more likely to give birth and raise children who will themselves be overweight or obese and, in turn, will have fewer chances of moving up the social ladder, perpetuating the link between obesity and socio-economic disadvantage [37,38]. Indeed, many studies show a complex link between socio-economic condition and obesity. However, the challenge is to understand what makes poorly educated individuals in disadvantaged socio-economic circumstances so vulnerable to obesity and those at the other end of the socio-economic side much able to handle obesogenic environments [39]. Evidence supports that – over long periods of time – more educated individuals are less likely to be become obese [40]. Educational programs aimed at promoting healthy lifestyles generate similar effects to those associated with school education by providing relevant information to tackle obesity [40]. Finally, weight tends to increase slightly, but progressively as individuals age, until it reaches a plateau and then begins to drop, around the fifth decade of life. Descriptive statistics tend to show an increase in obesity rates up to age 65–75 before the same rates start to decline [41]. The relationship between age and obesity is not just a reflection of individual biological features; it is also the reflection of changes in health related behaviors during the course of their lives. 4. Causes of obesity The underlying cause of obesity is a positive energy balance that follows excessive energy consumption and insufficient energy expenditure – or a combination of both [42]. Altered processes of hunger and satiety, reduced physical activity, and reduced ther-

mogenesis and resting metabolic rate over a prolonged period of time contribute to the energy imbalance. Currently, obesity is considered as a complex neuroendocrine disorder in which genetic predisposition and environmental factors act in concert [43,44]. Non-genetic risk factors comprise a wide range of environmental, social, physiological, and behavioral factors. Sedentary lifestyle and food over-consumption, particularly of high-fat and energydense foods, is largely responsible for the energy imbalance [16]. In addition, other external factors – age, gender, food preference, medications, socio-economic factors/status, and psychological attitudes – may give rise to weight gain and, therefore, increase the likelihood of obesity in individuals [16]. Heritability of obesity has been estimated by studies of twins, family, and adoptions and report a strong genetic component of around 60–90% [43]. The highest risk factor for childhood obesity is parental obesity [38,45] – especially maternal obesity [46] – suggesting an intrauterine and postnatal environmental dependent of genetic mechanisms [47]. Also, evidence points to a considerable genetic contribution to the responsiveness to regular physical activity [18] and eating behaviors [48]. The selection of nutrients appears to be partially heritable by genetic variables that mediate the consumption of sweet-tasting carbohydrate and fatty foods [49] and determine preference for these foods three times more frequently than in the individuals lacking these mutations [50]. Large-scale genetic studies reveal that genetic predisposition is due to the combined net effect of polygenic variants. Individuals carrying these variants may still not develop obesity, because they either lack other variants (gene–gene interaction) or are not exposed to risky environment (gene–environment interaction). Indeed, genetic susceptibility rarely causes obesity in the absence of obesogenic environmental. Whatever genotype influences on the onset of obesity, it is generally attenuated or exacerbated by nongenetic factors. Heritability of obesity goes beyond simple genetic markers and involves epigenetic mechanisms and lifestyle factors [51]. This is explained by Neel’s ‘thrifty genotype hypothesis’ [52], expanded by Chakravarthy [53] to include metabolic cycling and the dissonance between our stone-age genes with a space-age lifestyle. 4.1. Inflammatory components of obesity Adipocytes are the main cellular component of adipose tissues [54,55] and their major functions include thermogenesis, insulating, and padding, stuffing and cushioning internal organs, and energy storage in the form of triglycerides (TG) [56]. Furthermore, the adipose tissue is the largest endocrine organ in the body that secretes numerous cytokines (pro-inflammatory/proatherogenic) and adipokines (adiponectin, resistin) into the circulation altering body physiology in significant ways [57]. Also, the adipose tissue regulates intermediary metabolism and it is the target of hormones such as estrogens, androgens, growth hormone, and glucocorticoids [57]. In obesity phenotypes, the adipose tissue is influenced by diet and genes, as well as by their interactions [14,16]. In obese peo-

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ple’s adipocytes, we observe both hyperplasia and hypertrophy [58]. Also, the adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia) [59]. Both mechanisms can contribute to adipose tissue expansion; however, in adults, hypertrophy appears to predominate [60]. It has been found that hypertrophy is strongly correlated with diet whereas hyperplasia is dependent on genetics [58]. The number of adipocyte increases early in life, but reaches a maximum in early adulthood and then remains constant regardless of changes in weight [61]. In mild obesity, cells may become enlarged by the accumulation of lipids, without increasing in number; however as the degree of obesity increases to more serious levels of obesity, the number of adipocytes is always increased [61]. Adipocytes grow in size until they reach non-physiological limits. Then, such extremely swollen adipocytes become incapable to function as an energy storage organ, rapidly develop apoptosis, and change their endocrine function becoming resistant to insulin through two mechanisms: (a) ectopic translocation of free fatty acids and (b) adipose tissue inflammation. Additional fat from excess dietary lipids translocates to nonadipose tissues, e.g. liver, skeletal muscle, heart, and the ␤-cells of the pancreas where they exert toxic effects and trigger organ dysfunction [62]. This lipotoxicity may also be exacerbated by impaired oxidation of fat within tissues [62–64]. In this way, free fatty acids enter the skeletal muscle, where increased TG content is associated with decreased glucose uptake. Indeed, glucose entry in the cell is entirely controlled by insulin and also requires insulin receptors, a phosphorylative cascade, and trafficking of Glut-4 transporters, which are anchored to the membrane. The liver takes up glucose and synthesizes free fatty acids, releasing glucose when needed and free fatty acids as TG and VLDL, which also can be reused as energy sources. Overweight leads to fatty liver which increases hepatic glucose and VLDL production and, in turn, promotes the dyslipidemia characteristic of obesity and of the metabolic syndrome. One of the most severe forms of insulin resistance is found in lipoatrophic diabetes, where all TG can be recovered outside of adipocytes. The enlargement of the adipose tissue is also associated with the release of chemoattractant substances that set off an inflammatory process via activation of macrophages [57,65]. Extreme obesity increases adipocyte size and their degree of apoptosis, triggering a low-grade local inflammation and producing chronic adiposities (adipositis), sufficient to increase lipolysis through local paracrine effect of cytokines secreted by macrophages. Adipose tissue macrophages are highly inflammatory, secrete cytokines such as TNF-␣ and IL-6, and contribute to the recruitment of additional macrophages by secreting chemokines. Human studies demonstrate elevated gene expression of chemokines in obese adipose tissue, including MCP-1, MCP-2, MCP4, MIP-1␣, MIP-1␤, and MIP-2␣ [60]. A progressive infiltration of macrophages to the expanding adipose tissue results in a high increase in the number of macrophages, producing the formation of crown-like structures that surround the dead adipocytes. Accordingly, thin people have few resident macrophages in adipose tissue that do not secrete cytokines. In summary, obesity inflames fat tissues, producing chronic adipositis, macrophage accumulation in adipose tissue, and production of various cytokines that increase the local production of TNF-␣ and insulin resistance. This determines a low chronic inflammatory state that simultaneously activates mechanism by which cytokines are released into the bloodstream to the liver and immune cells increases levels of cytokines, hormone, and other inflammatory markers characteristic in obesity, metabolic syndrome, insulin resistance and diabetes conditions. In addition, endothelial cells secrete MCP-1 in response to cytokines. Whatever the initial stimulus to recruit macrophages into adipose tissue is, once these cells are present and active, they, along with adipocytes

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and other cell types, could perpetuate a vicious cycle of macrophage recruitment, production of inflammatory cytokines, and impairment of adipocyte function.

4.2. Neurological components The brain plays a relevant role in the regulation of appetite, body weight, and physical activity [66]. The neurogenetic etiology of obesity develops as a feedback system in which afferent signals inform the central controllers of the environment and provoke responses related to the regulation of food intake and energy metabolism [67]. The brain activates a system of energy-on-request to control its own energy; this system modulates behaviors such as allocative (energy assignment from body to brain), ingestive (energy intake from the immediate environment), or exploratory (foraging in the distant environment) ones, which are coordinated among brain regions involved in the eating process (cerebral hemispheres, hypothalamus, peripheral somatomotor, autonomic-visceromotor, and neuroendocrine-secretomotor neurons) [68]. Eating behavior is modulated by the brain reward systems through two mechanisms that act in concert. A mechanism that involves the homeostatic need to eat vs. another one involved with the hedonic and cognitive value of eating [69,70]. The hypothalamus [via regulatory neuropeptides such as leptin, cholecystokinin (CCK), ghrelin, orexin, insulin, neuropeptide Y (NPY), and through the sensing of nutrients, such as glucose, amino acids and fatty acids] is the brain region that chiefly regulates homeostatic food intake [71–73] and is implicated in obesity [74,75]. Moreover, the hypothalamus is also implicated in the rewarding effects of food joined to limbic [nucleus accumbens, hippocampus, amygdale] and cortical [orbitofrontal cortex, cingulate gyrus, insula] brain regions, as well as the neurotransmitter systems (dopamine, serotonin, opioids, cannabinoids) [76–78]. Lesions in the hippocampus impair rodents’ ability to discriminate between the state of hunger and that of satiety [79]. In humans, brain-imaging studies have reported activation of the hippocampus with food craving, a state of hunger, the response to food-conditioned cues and to food tasting [80]. Further studies showed that in obese – but not in lean persons – the hippocampus shows hyperactivation in response to those food stimuli [81]. Genetic defects affecting the center of hunger and satiety are the Prader-Willi (that causes an insatiable hunger and extreme obesity in childhood), the Bardet-Bield, the Cohen, and the AlströmHallgren syndromes. Numerous neural signals contributing to the regulation of food intake and energy homeostasis interfere with pathways involved in mood regulation and psychological traits [82]. The appetite-suppressing neuronal group produces proopiomelanocortin (POMC) that generates melanocyte-stimulating hormones (MSH). These hormones produce anoretic effects, i.e. reduce food intake, body weight, and increase energy expenditure in animals and humans. They activate their receptors located on surface brain and signal the rest of the brain that food is not needed. The appetite-stimulant neuronal group in which increased activity leads to orexigenic responses contains NPY and the agouti-related protein (AGRP) [83]. NPY potently stimulates food intake and reduces energy expenditure [83]. Appetite-stimulating neurons also produce the chemical neurotransmitter gamma-aminobutyric acid (GABA) that promotes eating by prompting food intake and sending signals that inhibit POMC activity from suppressing appetite [83] and prevents MSH production. Therefore, during periods of negative energy balance, appetite-stimulating NPY/AgRP molecules inhibit the message that no more food is needed in two ways: (a) by limiting production of MSH and (b) by preventing existing MSH from signaling. The interaction between NPY/AGRP

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(stimulating) and POMC (inhibiting) neurons in turn manages food intake. Several hormones are involved in regulating food intake by acting directly in the brain. Leptin is the primary homeostatic signal for the brain about the amount of energy stores and it activates hypothalamic centers that regulate energy intake and expenditure [82,84]. Leptin modulates neuronal activity in several regions of the central nervous system. Its major described action is on the hypothalamus through appetite inhibition effects, as well as stimulation of the metabolic rate and thermogenesis [85,86]. It appears that leptinergic and melanocortinergic signals act synergically, at least at the central level, and that leptin acts in the brain through the stimulation and/or potentiation of melanocortinergic transmission upon hypothalamic centers involved in feeding control [82]. In addition, leptin inhibits orexigenic transmitters, including NPY/AgRP, and stimulates anorexigenic transmitters, including the POMC. This setting can be displaced by extreme stress situations, drugs, hormones, exercise, and starvation. Leptin is a protein hormone produced mainly by white adipose tissue but evidence suggests that its biology (effects) extends to other organs including the kidney, heart, sympathetic nervous system, and the systemic vasculature [87–89]. Certain obesity cases are associated with mutations in leptin genes. Leptin treatment, particularly direct injection of leptin into the cerebral ventricle or hypothalamus, profoundly inhibits food intake and decreases weight and fat in animals lacking leptin. However, as obesity is associated with high leptin levels and not leptin deficiency, leptin treatment might eventually cure individuals with rare genetic types of obesity. Moreover, excess of leptin stimulates transport of macrophages to adipose tissue, thus contributing to their accumulation [65]. In addition to leptin, several other hormones are involved in regulating food intake by acting directly in the brain [83]. The gut produces several eating-related molecules included ghrelin. Researchers found that ghrelin activates the NPY/AgRP appetitestimulating neurons in response to negative energy balance. Ghrelin released by the gut enters the brain and stimulates a receptor on the NPY/AgRP cells that prompts secretion of growth hormone, thus increasing their appetite-stimulating activity. At the same time and related to this event, the mitochondrial machinery in the NPY/AgRP cells speeds up to deliver enough of the high-energy molecule ATP for cell metabolism. The enhanced mitochondrial activity also increases the production of harmful oxygen molecules derived from mitochondrial respiration. These harmful molecules are free radicals that react with other molecules inside the cell and promote cell damage. To protect the cell from such oxidative damage, the NPY/AgRP cells call on another mechanism to buffer these free radicals by activating the mitochondria uncoupling proteins (UCPs). With appropriate buffering of free radicals by the uncoupling proteins, the NPY/AgRP cells can maintain high firing rates, thereby stimulating food intake. 5. Pathologies associated with obesity In addition to mechanically affecting the body, i.e. by exacerbating osteoarthritis and back pain [6,90] because of the extra weight placed on the skeleton, obesity is associated with higher incidence of several severe pathologies (Fig. 2). We review the most important ones (at least from a numeric viewpoint). 5.1. Diabetes mellitus Accumulated data demonstrate the association between obesity, noninsulin-dependent diabetes mellitus – the most common primary form of diabetes – and impaired glucose tolerance

[91]. In obese individuals, the adipose tissue releases high amounts of non-esterified fatty acids, glycerol, pro-inflammatory cytokines, and hormones that are linked with the development of insulin resistance [92]. Insulin resistance generates compensatory hyperinsulinemia, with overstimulation of pancreatic ␤-cells and reduction of insulin receptors [92]. 5.2. Hypertension Insulin in excess alters Na+ and Ca2+ retention rates, in turn altering vascular reactivity and increasing cardiac output and peripheral resistance, which are the main components of blood pressure regulators. Epidemiological studies have demonstrated that between 65–75% of the risk for hypertension is accounted for by obesity [93,94]. Recently, endocrinological studies of the adipose tissue revealed tight links between obesity and hypertension, likely consequent to the fact that the adipose tissue secretes bioactive molecules and immunomodulators [95,96]. Out of these, leptin is endowed with significant pleiotropic actions on several organic systems [87,97]. In chronic hyperleptinemia and in obesity, we see the development of hypertension, and renal, vascular, and cardiac damage [98]. 5.3. Dislipidemia Obesity is the most common cause of dislipidemia. Lipid oversupply in a state of obesity, hyperinsulinemia, and/or insulin resistance results in increased non-esterified fatty acid availability and, in turn, higher TG stores [99–101] in non-adipose tissues, e.g. muscle, liver, pancreas. Fatty acid metabolites also accumulate and cause activation of signal transduction pathways that further induce inflammation and impair insulin secretion. Frequently, these fatty acid-induced disorders are referred to as “lipotoxicity” [62–64]. Thus, elevated TG level is often accompanied by a slight increase in total cholesterol and a marked drop in high-density lipoprotein (HDL) cholesterol. Moreover, low-density lipoproteins (LDL) rich in TG, partially metabolized by hepatic lipase, are converted into small LDL, with higher atherogenic potential [62–64]. This may be due to a higher prevalence of hypertension and proinflammatory/prothrombotic states associated with adipose tissue accumulation. 5.4. Cardiac alterations In general, obesity is an important determinant of cardiovascular diseases (CVD) [4,102] and increases the risk for heart failure, sudden cardiac death, angina or chest pain, and abnormal heart rhythm. Although heart failure is the most common cause of death in obese people, cardiomyopathy and sudden cardiac death also increase in healthy obese patients [103]. Evidence points to increased electrical alterations in obesity, which leads to frequent ventricular dysrhythmias even in the absence of heart dysfunction [104]. In the Framingham Heart Study [105], the annual sudden cardiac death rate was nearly 40 times higher in obese people than in a non obese population [104]. 5.5. The metabolic syndrome Obesity is considered the major components of the metabolic syndrome [106]. This syndrome is characterized by the cooccurrence of multiple metabolic disorders, namely overall and abdominal obesity, insulin resistance, hypertension, hyperglycemia, impaired glucose tolerance, and the combination of low HDL cholesterol and elevated TG level [107]. The metabolic

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Fig. 2. Consequences of obesity. The effects of obesity include medical co-morbidities, the psychological effects, the social effects and the effects on society as a whole. Genetic, environmental and other factors interact to influence body weight in a complex way.

syndrome is also characterized by prothrombotic and proinflammatory states [108]. 5.6. Lung diseases Obesity is associated with an increased risk for chronic respiratory disorders, including chronic obstructive pulmonary disease, asthma, hypoventilation syndrome, and sleep apnea. Accordingly, weight loss often leads to symptomatic improvement [5,109]. Respiratory disorders contribute to increased risk of hypertension, dysrhythmias, heart failure, stroke, myocardial infarction, and increased inflammation [110]; therefore, weight loss programs are mandatory in obese lung patients. 5.7. Cancer The link between obesity and cancer has been recently reviewed [111–113]. In contrast with cardiovascular disease and diabetes, obesity is less often indicated as a risk factor for many cancers. Even so, the International Agency for Research on Cancer classified the evidence of a causal link as sufficient for cancers of the breast, endometrial, colon, kidney, prostate, gallbladder, and esophagus although the biological mechanisms that explain this link are not known for any of these cancers [114]. The link between diet, obesity, and cancer is still not completely understood, but the rising worldwide trend in obesity and cancer might be – at least in part – causal. Indeed, overeating may be the largest avoidable cause of cancer in nonsmokers. While the putative cause of these obesity-related cancers has been primarily ascribed to excess estrogen production by adipose tissue, inflammation due to adipocytokines secreted by adipocytes, infiltrating macrophages or associated stromal cells might also play an important role [115]. Indeed, higher adipocytokine (leptin, hepatocyte growth factor, adiponectin) levels can negatively affect cell proliferation, apoptosis, invasive growth, and

angiogenesis. Obesity is associated with increased tumorigenesis that might explain the greater prevalence of neoplasia in obese individuals, who also have higher concentrations of inflammatory tumor growth factors [116]. 5.8. Neurological disorders Psychological damage caused by overweight and obesity carries a large health burden [117]. This disorder can range from lowered self-esteem to frank clinical depression [15]. Indeed, rates of anxiety and depression are three- to four-times higher among obese individuals [15]. The psychosocial aspects of obesity, often ignored in the drive to improve physical health, are particularly important in children [118]. Obesity significantly increases the risk of contracting Alzheimer’s disease. A strong correlation exists between BMI and high levels of ␤-amyloid, i.e. the protein that accumulates in the Alzheimer’s brain, destroying nerve cells and producing cognitive and behavioral problems. While the precise nature of this association remains obscure, physiological changes common to obesity may promote Alzheimer’s disease and dementia [8,119]. As an example, the FTO gene has a small but relevant effect on BMI and increases the risk for diabetes [120]. The Kungsholmen project, a prospective population-based study on 1003 persons without dementia, concluded that the FTO AA-genotype increases the risk for dementia and, in particular, Alzheimer’s disease, independently of physical inactivity, BMI, diabetes, and CVD [120]. 6. Dietary phytochemicals Dietary phytochemicals might be employed as anti-obesity agents, because they may suppress growth of adipose tissue, inhibit differentiation of preadipocytes, stimulate lipolysis, and induce

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Fig. 3. Classification of common dietary phytochemicals.

apoptosis of existing adipocytes, thereby reducing adipose tissue mass (Fig. 3). 6.1. Polyphenols Polyphenols are the more relevant family of phytochemicals endowed with health benefits [121]. Numerous preclinical studies reveal that selected polyphenols exhibit strong protective actions on many pathological conditions particularly those triggered by oxidative stress such as cardiovascular disease (CVD) and metabolic disorders. Moreover, dietary polyphenols may suppress growth of

the adipose tissue through their antiangiogenic activity and by modulating adipocyte metabolism [122,123]. Others benefits of polyphenols are related to infections, cancer, and autoimmune and neurodegenerative processes [124–127]. Polyphenols, including their functional derivatives – esters and glycosides – have one to various phenol groups with one hydroxylsubstituted aromatic ring [128]. According to their structure – number of phenol rings and the type and number of structural elements binding- polyphenols are grouped into different classes (Fig. 3): (1) simple phenolic acids, e.g. ferulic, caffeic, p-coumaric, vanillic, gallic, ellagic, p-hydroxybenzoic, chlorogenic acids; (2)

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stilbenes, e.g. resveratrol; (3) curcuminoids, e.g. curcumin; (4) chalcones, e.g. phlorizin, naringenin chalcone; (5) lignans, e.g. matairesinol, secoisolariciresinol; and (6) flavonoids, composed of seven subclasses: flavonols, e.g. quercetin, flavanols (monomeric, e.g. catechin, epicatechin, oligomeric, and polymeric compounds, e.g. proanthocyanidins, also called condensed tannins), anthocyanins, e.g. cyaniding, flavones, e.g. luteolin, apigenin, flavanones, e.g. naringenin, flavanonols, e.g. taxifolin, and isoflavones, e.g. genistein [121,129,130]. Simple phenolic acids are non-flavonoid phenolic compounds conjugated with other natural chemicals such as flavonoids, alcohols, hydroxyfatty acids, sterols, and glucosides. They are widely distributed into derivatives of benzoic acid (p-coumaric, caffeic, and ferulic acids) occurring most frequently as simple esters and as derivatives of cinnamic acid (ellagic, p-hydroxybenzoic, and gallic acids) mainly present in the form of glucosides. This polyphenolic group represents a substantial part of the human diet. Coffee beans and their soluble components are particularly rich in phenolic acids such as caffeic, ferulic, and p-coumaric acids. They are also found in potatoes, apples, blueberries, pomegranate, olive oil and wines, showing a wide range of pharmacological properties such as hypolipidemic, anticancer and anti-inflammatories [126,131–133]. Ferulic acid is one of the major phenolic compounds in rice bran oil and has strong in vitro antioxidant activities [134,135]. It is also found in others cereals such as wheat and oats and in coffee beans, apples, artichoke, peanuts, oranges, and pineapples [136]. Ferulic acid has hypolipidemic properties and could be effective in lowering the risk of high fat diet-induced obesity [137]. Also, it reduces serum cholesterol levels, protects against liver injury, and is a potent inhibitor of tumor promotion, at least in vitro [135,138]. Stilbenes naturally occur in a reduced number of plant species and are found as monomers, oligomers, and as conjugated to sugars. They are synthesized via the phenylpropanoid pathway in response to environmental stress, infections, disease, and excessive ultraviolet exposure [139]. These molecules are considered as phytoestrogen due to some structural similarities to estrogen and interact with estrogen receptors [140]. Resveratrol is found primarily in red grapes, apples, peanuts, blueberries, and cranberries, although in very low quantities [141]. Extensive literature describes its potent in vitro antioxidant properties and its potential to decrease LDL-cholesterol [142,143], prevent lipid oxidation, protect against the development of atherosclerosis and myocardial infarction, in addition to exerting anti-platelet and estrogenic activities [144,145]. The effects of resveratrol are consistent with its capacity to interact with molecular targets relevant during pathogenic processes [146], by inhibiting cyclooxygenase (COXs) and many pro-inflammatory mediators [147]. It exerts neuroprotection against amyloidal toxicity and increases brain activity [148,149]. Resveratrol produces favorable changes in genes expression and the activity of enzymes involved in metabolic syndrome [146,150]. Relevant to obesity, resveratrol decreases adipogenesis and viability in maturing preadipocytes by downregulating adipocytespecific transcription factors, and by altering the expression of adipocyte specific genes like PPAR␥, C/EBP␣, SREBP-1c, FAS, LPL, and HSL [22,151]. Moreover, resveratrol may alter fat mass by directly affecting biochemical pathways involved in adipogenesis in maturing preadipocytes. It increases the activity of enzymes related to calorie restriction (SIRT3, UCP1, and MFN2) in vitro in maturing preadipocytes [22,152]. In mature adipocytes, resveratrol increases lipolysis, induce apoptosis, and reduces lipogenesis and proliferation, thereby contributing to reduce lipid accumulation in vitro [22,153,154]. Also, resveratrol reduces the expression of mediators of the inflammatory response (TNF-␣, IL-6, and COX-2) in mature adipocytes, inhibits TNF-␣-activated NF-␬B sig-

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naling [142,151,155], and reverses the TNF-␣-induced secretion, and mRNA expression of PAI-1, IL-6, and adiponectin [156,157]. Furthermore, resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes by modification of Ser/Thr phosphorylation of insulin receptor substrate-1, and downstream AKT [156]. In human preadipocytes, resveratrol inhibits proliferation and adipogenic differentiation in a SIRT1 that promotes fat mobilization by repressing PPAR␥ [158]. In the mature human adipocytes, resveratrol increased insulin-stimulated glucose uptake, but, simultaneously, inhibits lipogenesis [158], reverses IL-1␤-stimulated secretion, and decreases gene expression of the pro-inflammatory adipokines IL-6, IL-8, MCP-1, and PAI-1 [157]. Dietary supplementation of resveratrol, vitamin D, quercetin, and genistein reduces weight gain and body fat [149,151,159]. Furthermore, resveratrol – in combination with genistein and quercetin – synergistically decreased adipogenesis in murine and human adipocytes. A recent in vivo study showed that resveratrol in combination with vitamin D prevented weight gain in rat model [151] leading to potential novel therapies for obesity. Curcuminoids are composed of two linked molecules of ferulic acid. The more abundant curcuminoids are curcumin, demethoxycucumin, and bisdemethoxycurcumin. They are non-toxic yellow pigment found in the Curcuma and Zingiber species, which are sources of the spices turmeric and ginger, respectively. Dietary curcuminoids possess a wide range of potentially beneficial properties, including anticancer, antiviral, anti-arthritic, anti-amyloidal, antioxidant, and anti-inflammatory activities [126,160–162]. Importantly, curcuminoids have been shown to prevent lipid accumulation in rats [163]. Of all curcuminoids, the best studied one is curcumin, derived from turmeric. Curcumin has the ability to regulate numerous molecular targets, including transcription factors (NF-␬B, STAT3, PPAR␥), growth factors (VEGF), inflammatory cytokines (TNF, IL-1, IL-6), protein kinases (mTOR, MAPK, Akt), other enzymes (COX2, 5LOX), and can also modulate other important signaling pathways mediated via AP-1, Bcl-2, Bcl-XL, caspases, IKK, EGFR, HER2, JNK, and Wnt/␤-catenin [161,164]. Curcumin regulates the expression of genes involved in energy metabolism and lipid accumulation, decreasing the level of intracellular lipids [165–167]. In adipose tissues, curcumin suppresses angiogenesis, which is necessary for tissue growth. Together with the effects on lipid metabolism in adipocytes, curcumin contributes to lower body fat and body weight gain [165]. Also, curcumin improves obesity-associated inflammation and associated metabolic disorders such as insulin resistance, hyperglycemia, hyperlipidemia, and hypercholesterolemia [168]. Curcumin protects from liver injury [169] preventing LDL oxidation by regulation of leptin – that helps to regulate energy intake- implicated in liver fibrosis [170]. Extensive investigation indicates that curcumin regulates expression of PPAR␥ and C/EBP␣, two transcription factors that play key roles in adipo- and lipogenesis [164,167,168]. Also, curcumin regulates gene expression of SREBPs, thus reducing cellular cholesterol and attenuating the stimulatory effects of LDL and leptin on hepatic stellate cells (HSC) activation [166,171]. Curcumin ameliorates some symptoms associated with diabetes and leptin-deficient as related in studies with mice [172,173]. Moreover, treatment with curcumin also significantly reduces macrophage infiltration of white adipose tissue, increases adipose tissue adiponectin production, and decreases hepatic NF-␬B activity and markers of hepatic inflammation [174]. Curcumin induces suppression of adipogenic differentiation by activation of Wnt/␤-catenin signaling [167,175]. Curcumin reduces body weight gain, adiposity, and microvessel density in adipose tissue, which coincides with reduced expression of VEGF and VEGFR2. Curcumin increases 5 -AMP-activated of

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AMPK, reduced GPAT-1, and increases CPT1 expression, which led to increased oxidation and decreased fatty acid esterification. Curcumin appears to be important in controlling adipocytes and cancerous cells by activation of AMPK, crucial for the inhibition of differentiation adipocytes and growth of cancer cells [176]. Curcumin directly interacts with adipocytes, pancreatic cells, hepatic stellate cells, muscles, and immune system macrophages [168]. This helps lowering leptin resistance, boosts adiponectin, and reduces multiple inflammatory signals associated with obesity including TNF-␣, IL-6, resistin, leptin, and MCP-1 [168]. Chalcones chemically consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon ␣,␤unsaturated carbonyl system [177]. They have been described as powerful anti-inflammatory, antioxidant, and anti-cancerigenic agents [177]. Other aspects of chalcones are their anti-estrogenic, anti-infective, anti-proliferative, anti-microbial, and anti-mitotic properties [177]. Belonging to this group is the dihydrochalcone phlorizin, used in the treatment of diabetes mellitus and obesity [178,179]. This flavonoid is abundant in the leaves of Sweet Tea (Lithocarpus polystachyus Rehd) [180] and is the principal phenolic glucoside in apple trees [181]. Its principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through non-specific inhibition of the sodium-glucose symporters (SGLT) located in the proximal renal tubule and mucosa of the small intestine [178]. Naringenin chalcones may be useful for ameliorating the inflammatory changes in obese adipose tissue. This chalcone has been reported to be a suppressor of inflammatory mediators production associated with the interaction of adipocytes and macrophages [182,183]. However, naringenin chalcone partly inhibit the degradation of I-␬B-␣ [182] and suppresses macrophage infiltration to hypertrophied adipocytes [184]. They are currently thought to affect the signaling molecules down-stream of TLR4, either directly or indirectly, but independent of PPAR␥ activation in macrophages [184]. Lignans are a group of phytoestrogen formed of two phenylpropane units. The most important sources of lignans are flaxseed and grain. Flaxseed (linseed) is the richest dietary source of lignans that contains secoisolariciresinol (>3.7 g/kg dry weight) and low quantities of matairesinol [185]. Others lignans have been identified in rye, e.g. pinoresinol, lariciresinol, isolariciresinol and syringaresinol [186]. Other sources of lignans are soya, sesame seed, berries, nuts, broccoli, tea, wine, and a variety of edible plant including algae, leguminous, cereals, vegetables (garlic, asparagus, carrots), and fruit (pears, prunes) [185]. There are two forms of lignans; plant lignans and mammalian lignans. When consumed, the plant lignans secoisolariciresinol and matairesinol are converted to the mammalian lignans enterodiol and enterolactone that have several biological activities, e.g. antioxidant (higher than that of vitamin E) and estrogen-like activities by which they may reduce the risk of chronic diseases included hormone-related obesity [187,185]. Intakes of matairesinol are inversely associated with coronary heart disease, CVD, cancer, and all-cause mortality [188]. Secoisolariciresinol diglucoside, was shown to reduce total serum cholesterol and atherosclerosis in rabbits [189], it has antihypertensive effects [190] and reduces the incidence of diabetes in several animal models [187,191]. In several human intervention studies, flaxseed reduces total and LDLcholesterol, without an influence on HDL or total TG [192]. Flavonoids constitute a large family of 6000 distinct phytochemicals identified in fruits and vegetables that have a common chemical structure. Current research focuses on their antioxidant [193] and anti-inflammatory [194] activities. Although flavonoids are generally considered to be non-nutritive agents, they are gaining interest because of their potential role in the prevention of

major chronic diseases (Table 1). They are might protect against cancer [126], and gastrointestinal [195], cardiovascular [196], and neurodegenerative [197] diseases. Flavonoids are classified into different subclasses, according to their chemical structure (Fig. 3). Flavonols are generally found in relatively low concentrations of 15–30 mg/kg fresh wt. The richest sources of flavonols are onions (up to 1.2 g/kg fresh weight), curly kale, leeks, broccoli, and blueberries. Red wine and tea also contain up to 45 mg flavonols/L, in glycosylated forms [198]. Observational and intervention studies have investigated the effect of flavonols on cardiovascular risk factors, including blood pressure, serum lipids, diabetes mellitus, and obesity [199]. Flavonols exert beneficial effects, including anti-inflammatory, anti-oxidant, and anti-proliferative effects, as well as favorable effects on endothelial function and they interfere with a large number of biochemical signaling pathways and, therefore, with physiological and pathological processes [199,200]. Human intervention trials with isolated flavonols demonstrate an antihypertensive effect [199]. A meta-analysis of epidemiological studies shows an inverse association between flavonol – together with flavones – intake and coronary heart disease and stroke [199]. Quercetin, in particular, exhibits higher anti-lipase activity (27.4%) than luteolin (17.3%) at 25 mg/mL [201] and attenuates in vitro adipogenesis by activating the AMPK signal pathway in preadipocytes and decreased expression of adipogenesis-related factors [202]. Quercetin induces apoptosis in preadipocytes by decreasing mitochondria membrane potential, down-regulating PARP and Bcl-2, and activating caspase-3, Bax, and Bak [203], and induces apoptosis of mature adipocytes by modulation of the ERK and JNK pathways, which are relevant during apoptosis [202]. Flavanols exist as monomers (catechins) and polymers (proanthocyanidins). Catechins are found in many types of fruits (apricots, which contain 250 mg/kg fresh wt, are the richest source) and in red wine (up to 300 mg/L), but green tea and chocolate are by far the richest sources. An infusion of green tea contains up to 200 mg catechins [204]. A human study has shown that after three months of intervention an extract standardized at 25% catechins decreased body weight by 4.6% and waist circumference by 4.48% [205]. This was proposed to be acting by inhibiting gastric lipases and increasing thermogenesis [205,206]. Green tea catechins, especially epigallocatechin gallate (EGCG), have been demonstrated in cell culture and animal models of obesity to reduce adipocyte differentiation and proliferation, lipogenesis, fat mass, body weight, fat absorption, plasma levels of TG, free fatty acids, cholesterol, glucose, insulin and leptin, as well as to increase ␤-oxidation and thermogenesis [207,208]. They significantly reduce intracellular lipid accumulation and repressed the activity of glycerol-3-phosphate dehydrogenase, enzyme involved in lipid synthesis [209]. Furthermore, glucose and fatty acid transport were also suppressed. EGCG induced the insulin signal-mediated phosphorylation of factors-forkhead transcription factor class O1 (FoxO1) [209]. EGCG suppresses the differentiation of adipocytes through the inactivation of FoxO1 and SREBP1c, which are involved in adipocyte differentiation and lipid synthesis, respectively [209]. EGCG also induced apoptosis in preadipocytes. The apoptotic effects were Cdk2 and caspase-3 dependent and could be attributed to inhibition of cell mitogenesis. Adipose tissue, liver, intestine, and skeletal muscle are target organs of green tea, mediating its anti-obesity effects [207]. These effects may be mediated by decreased lipid absorption, decreased inflammation, and other mechanisms [210,211]. As preventive agent anti-obesity, EGCG has been studied in rodents [207,212]. Evidence exists that indicate that long-term EGCG treatment attenuates the development of obesity, symptoms associated with the metabolic

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Table 1 Beneficial effects of some flavonoids on obesity and associated diseases, in humans. Bioactive compound

Model (treatment dosage and duration)

Beneficial effects

Epigallocatechin gallate

Obese men (300 mg/day, 3 days) Obese men (800 mg/day, 8 weeks) Isolated human adipocytes (100 ␮M)

Postprandial RQ decrease Blood pressure decrease TG accumulation decrease Normalizing adipocytokine secretion Inflammation decrease

Soy isoflavones mixture

Postmenopausal women (75 mg/day, 6 months)

Genistein

Postmenopausal women (>1 mg/day)

BMI decrease Body fat mass decrease Blood HDL increase BMI decrease Body fat mass decrease Waist size decrease Blood HDL increase Blood HDL increase Fasting insulin decrease Blood lipids decrease

Cyandin and cyanidin 3-glucoside

Naringin Quercetin Berberine Resveratrol

Postmenopausal women (0.001–0.999 mg/day) Hypercholesterolemic subjects (400 mg/day, 8 weeks) Men and women, stage 1 hypertension (730 mg/day) Hypercholesteromic patients (1 g/day, 3 month) Human platelet (0–100 ␮M)

Mechanisms of action (molecular targets)

Adipogenic transcription factor (C/EBP␣) mRNA increase Adipocytokine expression change (adiponectin increase; PAI-1and IL-6 decrease) Lipolysis and fatty acid oxidation increase (UCP2, acylCoA oxidase 1, perilipin increase)

ApoB decrease

Blood pressure decrease Blood lipids decrease Platelet aggregation decrease

Adapted from [20].

syndrome, and fatty liver. EGCG treatment appeared to reverse preexisting high-fat-induced metabolic pathologies in obese mice and results from human intervention trials have shown that consumption of green tea catechins may reduce body weight and fat [213,214]. A proposal possible mechanism is that these compounds influence sympathetic nervous system activity, increasing energy expenditure and promoting fat oxidation [208,213]. Caffeine, naturally present in green tea, also influences sympathetic nervous system activity, and may act synergistically. In humans EGCG in combination with caffeine can increase fat oxidation and energy expenditure [215] and reduce total and abdominal fat [216]. Proanthocyanidins, known as condensed tannins, are dimers, oligomers, and polymers of catechinods found in many plants, most notably apples [217], maritime pine bark, cinnamon, cocoa, grape seed, grape skin (procyanidins and prodelphinidins) [218], and red wines. Moreover, bilberry, cranberry, green and black teas, and other plants also contain these flavonoids [217]. These compounds are responsible for the astringent character of fruit and for the bitterness of chocolate. The content in foods of proanthocyanidin is difficult to estimate due to the variety of their structures and molecular weights [219]. Importantly, proanthocyanidins inhibit inflammatory genes expression and modulate the intracellular antioxidants level that protects from ischemia and cardiovascular disease [220]. Grape seed proanthocyanidins stimulate long-term lipolysis by increasing cAMP and PKA in 3T3-L1 adipocytes [221]. Although very abundant in the diet, proanthocyanidins are very poorly absorbed and their action is restricted to the intestine [222]. Anthocyanins are antioxidants pigments that exist in different chemical forms. They are highly unstable in the aglycone form (anthocyanidins) and are resistant to light, pH, and oxidation condition while they are in plants. Anthocyanins are stabilized by the formation of complexes with other flavonoids (co-pigmentation) and their degradation is prevented by glycosylation and esterification with various organic acids (citric and malic acids) and phenolic acids. In the human diet, anthocyanins are found in red wine, certain cereals, and certain leafy and root vegetables (eggplant, red cabbage, beans, onions), although they are most abundant in fruits (apples, blueberries, purple grapes) [223].

Cyanidin is the most common anthocyanidin in foods. Its food contents are generally proportional to color intensity and reach values up to 2–4 g/kg fresh wt in blackberries. Wine contains ∼200–350 mg anthocyanins/L [223]. These flavonoids have been shown to have anti-inflammatory activity in obese adipose tissues, which is mediated by PPAR␥-independent mechanisms [224]. Moreover, cyanidin 3-glucoside (C3G) down-regulates the RBP4, which is known to ameliorate insulin sensitivity in the adipose tissue of diabetic mice [225]. Flavones are much less common than flavonols in fruit and vegetables. Natural flavones consist of glycosides of luteolin and apigenin. The only important edible sources of flavones identified to date are parsley and celery. Cereals such as millet and wheat contain C-glycosides of flavones [226]. The skin of citrus fruit contains large quantities of flavones tangeretin, nobiletin, and sinensetin [227]. The flavones luteolin and apigenin appear to inhibit CAM gene expression, increased in obesity processes, by blunting the activation of NF-␬B stimulated by TNF-␣. These inhibitory mechanisms of the flavones appear to be independent of an antioxidant effect and may argue for transcriptional mechanisms as the major target of the anti-atherogenic action of flavones. Luteolin exhibits antioxidant and anti-inflammatory activities [228]. In particular, luteolin have been found be an immune system modulator that reduces brain inflammation with important implications in various neurodegenerative disorders [229]. Also, it inhibits proliferation of human leukemia cells and plays an important role as promoter of carbohydrate metabolism [230]. Recently, it has been found that luteolin inhibits low-grade chronic inflammation induced during the coculture of adipocytes and macrophages [231], and prevent the phosphorylation of JNK in macrophages activated from adipocytes [184,231]. Luteolin exhibits anti-lipase activity (17.3%) and enhanced insulin sensitivity via activation of PPAR␥ transcriptional activity in adipocytes [201]. Flavanones are found in tomatoes and certain aromatic plants such as mint, but they are present in high concentrations only in citrus fruit. The main aglycones are naringenin in grapefruit, hesperetin in oranges, and eriodictyol in lemons. Orange juice

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contains between 200 and 600 mg hesperidin/L and 15–85 mg narirutin/L [232]. The maximum concentrations of hesperetin metabolites determined in plasma 5–7 h after intake of orange juice are 1.3–2.2 ␮mol/L for an intake of 130–220 mg [233]. The flavanone naringenin is especially abundant in the Mediterranean diet (citrus fruits and tomatoes). In appears to be better absorbed when given though grapefruit juice: a plasma concentration of 6 ␮mol/L can be attained after ingestion of 200 mg. Naringenin inhibits induced inflammation in coculture of adipocytes and macrophages [182] and has estrogen agonistic and antagonistic activities in distinct types of cells [234]. This flavanone improves the immunosuppressive environment through downregulating transforming growth factor-B1 (TGF-B1) and reducing regulatory T cells. Naringenin acts as an antioxidant by indirect modulation on the metabolism of many xenobiotics and as a cholesterol-lowering agent by inhibiting cholesteryl ester synthesis [235]. Furthermore, naringenin appears to affect different oxidative processes associated with chronic degenerative diseases. In fact, it restores glutathione-dependent protection against lipid peroxidation in ␣-tocopherol-deficient liver microsomes [236]. Naringenin also decreases preadipocyte proliferation similarly to rutin, hesperidin, and naringin [203]. In summary, there is promising evidence for naringenin to prevent weight gain and other components of metabolic syndrome that can lead to type 2 diabetes and increased risk of CVD. Flavanonols are a class of flavonoids that differ in their oxidation state from anthocyanins and that have a 3-hydroxy-2,3-dihydro-2phenylchromen-4-one backbone. Some examples include taxifolin (dihydroquercetin) and aromadedrin (dihydrokaempferol). Taxifolin exhibits anti-inflammatory activities in vitro [237] and inhibits cholesterol synthesis by suppression of HMG-CoA reductase activity. It also prevents the synthesis and secretion of triacylglycerol and phospholipids and decreases the secretion of apoB into LDL-like particles [238]. Isoflavones are diphenolic compounds with chemical structures similar to that of estradiol, which binds to estrogen receptors. They are commonly referred to as estrogen-like molecules or nonsteroidal estrogens. They may activate genomic and non-genomic estrogen signaling pathways and interact with the metabolism of steroid hormones [239]. Soy is the main source of isoflavones in the human diet. Soy beans contain between 580 and 3800 mg isoflavones/kg fresh wt and soy milk between 30 and 175 mg/L [240]. Soy isoflavones are made up by three principal molecules: genistein, daidzein, and glycitein, generally in a concentration ratio of 1:1:0.2 [222]. Beside their purported health benefits related their protective roles toward hormone-dependent cancers, i.e., prostate and breast cancer isoflavones might protect against obesity and CVD [241]. A diet with high proportions of soy was reported to increase HDLcholesterol and decrease total cholesterol, LDL-cholesterol, and plasma TG levels [239]. Genistein and daidzein suppress adipogenic differentiation of adipose tissue derived of mesenchymal stem cells that secrete angiogenesis-related cytokines and inhibit expression of adipogenic markers, PPAR␥, SREBP-1c, and Glut-4 [242]. Genistein also decreases preadipocyte proliferation; its anti-adipogenic effects are thought to be principally mediated by the activation of Wnt signaling via ERs-dependent pathways such as Erk/JNK signaling and LEF/TCF4 co-activators [242]. Furthermore, genistein in combination with resveratrol and quercetin synergistically decreased adipogenesis in murine and human adipocytes [22]. Studies in vitro have showed that genistein in combination with vitamin D potentiates the inhibition of adipogenesis and the induction of apoptosis in maturing preadipocytes [22]. Therefore, some combinations of phytochemicals may lead to potential novel therapies for obesity. Moreover, consumption of soy protein isolate or soy isoflavone

genistein modulates mRNA expression of genes underlying lipid and thyroid hormone metabolism in livers and small intestines of rats [243]. Effects of soy protein isolates and genistein contribute to the reductions in body weight, abdominal fat pad weight, and hepatic content of lipid droplets and TG, and adipose tissue weight and liver lipid content in animal models [243]. Capsaicin is an alkaloid found primarily in red hot peppers, which provides their spicy flavor. This phytochemical has been attributed pharmacological effects since ancient times, but extensive research has also been performed to find specific applications for its activities. Examples include the gastrointestinal tract, weight-loss, and analgesic actions [244]. Capsaicin can attenuate not only obesity-induced inflammation, but also obesityrelated metabolic disorders and liver diseases [245,246]. Capsaicin suppresses obesity-induced inflammatory responses by reducing levels of TNF␣, IL-6, and MCP-1, and enhances adiponectin levels in adipose tissue and liver, which are important for insulin response [245,246]. These beneficial effects are associated with the dual action of capsaicin on PPAR␥/PPAR␣ and TRPV-1 expression/activation associated with NF-␬B inactivation and PPAR␥ activation [246]. Moreover, capsaicin suppresses macrophage migration induced by the adipose tissue and macrophage activation. The induction of apoptosis in 3T3-L1 preadipocytes by capsaicin is mediated through the activation of caspase-3, Bax, and Bak and through the cleavage of PARP and the down-regulation of Bcl-2 [203]. In addition, capsaicin induced a reduction of food intake and increased energy expenditure and lipid oxidation in rats [247,248]. In humans, a significant increase in energy expenditure was observed immediately after a meal containing red pepper vs. control [249]. In addition, both animal and human studies show that thermogenesis can be induced by capsaicin upon ␤-adrenergic stimulation and, in rats, through enhancement of catecholamine secretion from the adrenal medulla [250]. Animal studies also show that treatment with capsaicin stimulates the sympathetic nervous system activity, suggesting that specific capsaicin-sensitive neurons are involved in this process [247,248,250]. In a 2-week human study, administration of capsaicin in combination with green tea and chicken essence induced reduction in body fat [251]. Thus, administration of capsaicin favors an increase in lipid mobilization and a decrease in adipose tissue mass [248]. 6.2. Terpenoids (isoprenoids) Terpenoids (isoprenoids) constitute one of the largest families of natural products, accounting for more than 40,000 compounds of both primary and secondary metabolisms [252]. Terpenoids can be described as chemically-modified terpenes. Many terpenes are hydrocarbons, but they also have oxygen-containing compounds such as alcohols, aldehydes, and ketones (terpenoids) [20]. The simplest unifying feature present in the structure of all terpenoides is the isoprene unit (CH2 C(CH3)–CH CH2). Based on the number of carbon atoms, terpenoids can be classified into further groups: hemiterpenoid (C5), monoterpenoids (C10), sesquiterpenoids (C15), diterpenoid (C20), sesterterpenoid (C25), triterpenoids (C30), tetraterpenoid (C40), and politerpenoid (C> 40). Most of the terpenoids are of plant origin and are present in vegetables and fruit. Daily eating of certain terpenoids might be useful for the management for obesity-induced metabolic disorders, such as type 2 diabetes, hyperlipidemia, insulin resistance, CVD, and a lower prevalence of metabolic syndrome [252]. PPAR␥ activation attenuates obesity and type-2 diabetes. Geranylgeraniol, farnesol, and geraniol terpenoids are ligands with potential to activate PPAR␥, dietary lipid sensors that control energy homeostasis and lipid and carbohydrate disorders [253,252]. At 100 ␮M, i.e. non-physiological concentrations, the

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activations of PPAR by geraniol, farnesol, and geranylgeraniol were found to be 2.2-, 4.1-, and 3.7-fold that of the control, respectively [253]. Several reports have indicated that co-application of PPAR␣ and PPAR␥ agonists causes more efficient glucose uptake into adipocytes to decrease blood glucose levels without a concomitant increase in body weight [254]. In this regard, farnesol and geranylgeraniol isoprenols have the effects of dual activation of PPAR␥ and PPAR␣ [253]. The monoterpene derivative auraptene, a citrus fruit compound mainly contained in the peel, is also a PPAR␣/␥ dual agonist [255,256]. In adipocytes, auraptene regulates the transcription of PPAR␥ target genes, induces the expression of adiponectin, and inhibits those of MCP-1 [256]. It was also observed that auraptene suppresses the inflammatory signaling exchange between adipocytes and macrophages and the macrophagic infiltration into obese adipose tissues [254]. Sesquiterpenes from plants comprise a group of substances with biological effects such as antiviral, anti-inflammatory, analgesic, and cytotoxic ones [257]. These biological activities are generally the result of reactions of sesquiterpernes with the thiol groups of enzymes. The anti-inflammatory activities of some medicinal plants result from the presence of one or more sesquiterpene lactones [257]. Abscisic acid (ABA) is a natural sesquiterpene that has shown efficacy in the treatment of diabetes and obesity-related inflammation. In fact, ABA has structural similarities to conventional thiazolidinedione diabetes drugs; dietary intake of ABA was found to decrease fasting luminal glucose concentrations in mice [258]. Surprisingly, it has been suggested that ABA is an endogenous pro-inflammatory cytokine in human granulocytes and that it can stimulate the secretion of insulin in pancreatic ␤-cells [259]. The lowest effective dose of dietary ABA (100 mg/kg for 36 days) decreased fasting blood glucose levels, improved glucose intolerance, obesity-related inflammation, and mRNA expression of PPARg and its responsive genes in white adipose tissue (WAT) of db/db mice fed high-fat diets [258]. Adipocyte hypertrophy, TNF-␣ expression, and macrophage infiltration in adipose tissue are significantly attenuated under ABA intake [258]. Recent works demonstrate that ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domainindependent mechanism of PPAR␥ activation. LANCL2 represents the first step in a pathway that activates PPAR␥ in immune cells by ABA [260]. The ABA influence on the expression of several genes involved in inflammation, metabolism, and cell signaling provides further ground for potential treatments of inflammatory and immune-mediated diseases [260]. Carotenoids are lipophilic pigments tetraterpenoids. Their most characteristic structural feature is the long series of conjugated double bonds in the central part of the molecule, vulnerable to oxidation and cis–trans isomerization. This gives them their shape, chemical reactivity, and light-absorbing properties [261]. More than 700 naturally occurring carotenoids, widely distributed in plants, microorganisms, and animals, have been identified [261]. Carotenoids are classified into hydrocarbons (carotenes) and their oxygenated derivatives (xanthophylls). They are responsible for the yellow, orange, and red color of many fruits, vegetables, a few roots, egg yolk, fish like salmon and trout, and crustaceans. Carotenes (or carotin) such as ␣-carotene, ␤-carotene, and lycopene also serve as precursors for vitamin A and play important roles in the immune response, vision, and cellular differentiation. The main xanthophylls include lutein, zeaxanthin, axthaxanthin, neoxanthin, violaxanthin, and ␣- and ␤-cryptoxanthin. Carotenoids are essential components of the human diet as they are precursors for vitamin A biosynthesis in addition to being powerful antioxidant agents [262]. Studies suggest that carotenoids may prevent the development of inflammation-associated diseases such as obesity and atherosclerosis [263,264].

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␣-Carotenes is one of the most abundant carotenoids in the diet and can be converted in the body to an active form of vitamin A. ␤-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages, and has been suggested that its antioxidant activity contributes to beneficial effects on CVD. Both ␣- and ␤-carotene are found in carrots, pumpkin, sweet potatoes, broccoli, spinach, pumpkins and leaf lettuce and apricots. Significantly lower levels of plasma carotenoids (␣-carotene, ␤carotene) were found among overweight and obese children when compared to healthy weight children [265]. High waist circumference has been associated with low levels of serum canthaxanthin and ␤-carotene. High waist hip ratio was also associated with low levels of serum ␣-carotene and ␤-carotene. Similar results were obtained when body mass index was added to confounding factors. In males, however, there were no significant associations between obesity indices and serum levels of carotenoids [266]. Lycopene, a red carotenoid mainly found in tomatoes, red peppers, and some fruits including watermelon and pink grapefruits, is fat-soluble and heating process makes it more easily absorbed [267]. Lycopene is a powerful antioxidant with a strong ability to scavenge free radicals and, because of its high number of conjugated dienes, is the most potent singlet oxygen quencher among the natural carotenoids [268]. Diets rich in lycopene have been associated with lower risk of CVD. Lycopene has been suggested to have several mechanisms of action including inhibition of LDL oxidation and lipid peroxidation [269]. Recent studies have demonstrated that mechanisms other than the antioxidant ones are responsible for the biological activities of lycopene. Examples include intercellular gap junction communication, hormonal and immune system modulation, induction of phase II enzymes, suppression of insulin-like growth factor-1-stimulated cell proliferation, antiangiogenesis and inhibition of cell proliferation; and induction of apoptosis [270]. The low-level inflammation induced by the massive development of adipose tissue in obese individuals contributes to promotion of insulin resistance and type 2 diabetes. Lycopene is mostly stored in adipose tissue and possesses anti-inflammatory properties. Indeed, it reduces the production of pro-inflammatory markers such as IL-6, MCP-1 and IL-1␤ at the mRNA and protein level in adipose tissue in vitro and ex vivo [271]. Lycopene preincubation for 24 h decreased the TNF␣-mediated induction of IL-6 and MCP-1. In both preadipocytes and differentiated 3T3-L1 adipocytes and human adipocyte primary cultures [271]. In transient transfections, the involvement of the NF-␬B pathway was confirmed in the decrease of the luciferase gene by the modulation of IKK␣/␤ phosphorylation in cells incubated in the presence of lycopene [271]. 6.3. Organosulfurs Organosulfur compounds are particularly abundant in Allium vegetables including garlic, onion, scallion, chive, shallot, and leek that contain bioactive substances such as allicin, allixin and allyl sulfides [272]. These molecules account for the distinctive flavor and aroma as well as the many purported medicinal effects of these vegetables. Organosulfurs provide glucosinolates, which are converted in the human body in thiosulfonates, indoles (indole-3carbinol), an isothiocyanates [273]. Organosulfurs from garlic and onions have been reported to exert various physiological obesity related effects. They decrease the synthesis of cholesterol by hepatocytes through inhibition of HMG-CoA reductase, a critical enzyme in the cholesterol biosynthesis pathway. Organosulfurs also lower blood pressure and stimulate non-specific immunity [274]. They are heralded as powerful anti-thrombic, hypoglycemic, and lipid-lowering agents.

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Also, they prevent platelet aggregation and are attributed with liver protection and immune system strengthening activities [272,273]. Garlic-derived organosulfur compounds have been found to inhibit the activity of the inflammatory enzymes, cyclooxygenase and lipoxygenase, in vitro [273] and to decrease the expression of inducible nitric oxide synthase (iNOS) in macrophages [273]. Organosulfur compounds have also been found to decrease the production of inflammatory signaling molecules in cultured macrophages and human whole blood [273]. Finally, although the beneficial effects of organosulfurs have been mostly ascribed to their antioxidant and anti-carcinogenic properties [272], the adipocyte-specific effects of ajoene, a garlic derivative, were also reported [275]. In particular, garlic extracts may decrease fat cell number, thereby suggesting some therapeutic possibility for obesity.

6.4. Phytosterols Phytosterols are natural compounds structurally similar to mammalian cell-derived cholesterol [276]. These phytochemicals including sterols and stanols; the latter are the form predominantly occurring in nature [277]. The best dietary sources of phytosterols are unrefined vegetable oils, seeds, cereals, nuts, and legumes; they exist in both esterified and free alcohol forms [278]. Phytosterols with potential effects on obesity are diosgenin, campesterol, brassicasterol, sitosterol, stigmasterol, and guggulsterone. High intakes of these compounds can also protect against atherosclerosis [279] and decrease serum total and LDL-cholesterol levels [280]. Mechanistically, phytosterols compete with cholesterol for micelle formation in the intestinal lumen and inhibit cholesterol absorption [280]. Their influence on intestinal genes and transcription factors make phytosterols key regulators in metabolism and cholesterol transport in the expression of liver genes [276,281]. In terms of phytotherapy, furostanol saponin is the active ingredient of the rhizomes of Dioscorea gracillima, the protodioscin studied for its anti-hyperlipidemic effect. The administration of protodioscin in hyperlipidemic rats significantly reduced the blood levels of TG, cholesterol, low- and high-density lipoproteins [282]. Acid hydrolysis of this bisdesmoside forms diosgenin, a phytoestrogen that can be chemically converted into progesterone [283]. Diosgenin is found in a variety of plants, including fenugreek and the roots of wild yam. Diosgenin has various biological functions, including anti-inflammatory roles via down-regulation of I-␬B-␣ degradation and JNK activation [284], which is independent of PPAR␥ activation [285]. Diosgenin (5 and 10 ␮mol/L) inhibited the accumulation of TG and the expression of lipogenic genes in HepG2 cells [285]. Also, diosgenin is used for hypercholesterolemia and diabetes treatments, and it possesses anti-thrombosis effects in vitro and in vivo [286]. A phytosterol used as an effective non-toxic herbal medicine for obesity, arthritis, cancer, and CVD is guggulsterone, the active agent of the guggul plant (Commiphora mukul) [287]. Its most studied effects are related to lipid, cholesterol, TG, and glycemia lowering and serum high density lipoprotein rising. Thereby, this plant is considered as a potential anti-obesity agent [288–290]. Guggulsterone is a selective bile acid receptor modulator that regulates expression of a subset of farnesoid X receptor (FXR) targets and decreases the expression of bile acid-activated genes [290]. In addition, guggulsterone may modulate anti-inflammatory and antioxidant responses mediated through the inhibition of NF␬B [291,292]. Finally, guggulsterone demonstrated significantly improved PPAR␥ expression and activity in vivo and in vitro, in addition to inhibiting adipocytes differentiation in vitro [293].

7. Conclusions and future directions As mentions, obesity is reaching epidemic proportion and needs to be aggressively targeted by basic scientists, physicians, and health authorities. Indeed, excessive accumulation of fat leads to a chronic low-grade inflammatory state associated with high circulating levels of inflammatory markers, such as cytokines and proteins, insulin resistance and CVD. While the etiology of obesity is multi-faceted, low-grade inflammation is common and represents a potentially useful and general target. In this respect, several phytochemicals have been shown to possess anti-inflammatory effects and might be exploited in the adjunct therapy of obesity. In addition, several molecules found in foods and plants induce apoptosis, decrease lipid accumulation, and induce lipolysis. As complex and interconnected cell signaling pathways are involved in the development and maintenance of obesity, the use of multiple phytochemicals might result in synergistic and enhanced effects. Future investigations will eventually verify if the multitude of salubrious actions investigated in vitro do translate into in vivo actions, especially in humans. Conflict of interests The authors declare no conflict of interest. Acknowledgements This work has been supported by the Spanish Ministry of Science and Innovation (R&C2007-01920) and the Regional Government of Madrid (CPI/0631/2008). References [1] World Health Organization. Obesity: preventing and managing the global epidemic – report of a WHO consultation on obesity. Geneva, Switzerland: WHO; 1998. [2] Popkin BM. The world is fat: the fads, trends, policies, and products that are fattening the human race. New York: Avery Trade/Penguin Group; 2009. [3] Singla P, Bardoloi A, Parkash AA. Metabolic effects of obesity: a review. World J Diabetes 2010;1(3):76–88. [4] Marinou K, Tousoulis D, Antonopoulos AS, Stefanadi E, Stefanadis C. Obesity and cardiovascular disease: from pathophysiology to risk stratification. Int J Cardiol 2010;138:3–8. [5] Piper AJ. Obesity hypoventilation syndrome – the big and the breathless. Sleep Med Rev 2011;15(2):79–89. [6] Roffey DM, Ashdown LC, Dornan HD, Creech MJ, Dagenais S, et al. Pilot evaluation of a multidisciplinary, medically supervised, nonsurgical weight loss program on the severity of low back pain in obese adults. Spine J 2011;11(3):197–204. [7] Derdemezis CS, Voulgari PV, Drosos AA, Kiortsis DN. Obesity, adipose tissue and rheumatoid arthritis: coincidence or more complex relationship? Clin Exp Rheumatol 2011. PMID:21640051. [8] Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67(6):505–12. [9] Withrow D, Alter DA. The economic burden of obesity worldwide: a systematic review of the direct costs of obesity. Obes Rev 2011;12(2):131–41. [10] Popkin BM, Kim S, Rusev ER, Du S, Zizza C. Measuring the full economic costs of diet, physical activity and obesity-related chronic diseases. Obes Rev 2006;7:271–93. [11] National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: the evidence report. Obes Res 1998;6(Suppl 2):51S–209S. [12] Timar R. Obezitatea adultului. In: Serban V, Babes PA, editors. Clinica Medicala. Teorie si practica, Editura de Vest, Timisoara; 1999. p. 83–198. [13] Aronne LJ. Classification of obesity and assessment of obesity-related health risks. Obes Res 2002;10:S105–15. [14] Ordovás JM, Shen J. Gene–environment interactions and susceptibility to metabolic syndrome and other chronic diseases. J Periodontol 2008;79(8 Suppl):1508–13. [15] International Obesity Task Force [IOTF]. http://www.iotf.org/. [16] Marti A, Martinez-González MA, Martinez JA. Interaction between genes and lifestyle factors on obesity. Proc Nutr Soc 2008;67(1):1–8. [17] Smith CE, Ordovás JM. Fatty acid interactions with genetic polymorphisms for cardiovascular disease. Curr Opin Clin Nutr Metab Care 2010;13(2):139–44.

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