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Metabolic syndrome: molecular basis and reasons for interaction with obesity/ Sindrome metabolica: bases moleculares e fundamentos da interacao com obesidade.

Introduction

This review aims to present and discuss studies that characterize the metabolic syndrome (MS) and its relationship with obesity. We analyze works that address the physical, clinical, biochemical and genetic aspects of this syndrome and shed light on its molecular bases, which have lately been unveiled and dissected in order to better understand adipogenesis and obesity.

In adult humans, the accumulation of multiple cardiovascular risk factors had already been observed since the early 20th century. (1, 2) More recently, though, similar clusters of certain cardiac factors have received renewed attention and terms such as deadly quartet, (3) insulin-resistance syndrome, (4) Metabolic Syndrome (MS), (5) syndrome X, (6) or plurimetabolic syndrome have been proposed to describe the connection between obesity, insulin resistance, systemic arterial hypertension (SAH), dyslipidemia, type 2 diabetes mellitus (T2DM), and atherosclerotic cardiovascular disease (ASCVD). Thus, we can say that the definition of this syndrome varies in terms of which indicators are present and which cut-off values are used. (2)

Recent evidence, however controversial it may be, (7) has emerged with substantial information on childhood obesity in association with insulin resistance, inflammation and other risk factors and on their collective role in the increased risk of ASCVD and T2DM. The constellation of these interrelated cardiovascular risk factors in adults came to be known as the metabolic syndrome (MS), a designation that has proven to be useful both in clinical and research settings (2) and that has recently been updated according to global consensus guidelines for its study, diagnosis and prevention. (8, 9) With this in mind, MS has been characterized by the occurrence of complex disorders represented by a cluster of cardiovascular risk factors commonly associated with central adiposity and insulin resistance. (10)

Other conditions associated with MS include physical inactivity, aging, hormonal imbalance and genetic predisposition. Some people are genetically susceptible to insulin resistance. However, such factors as excess body fat and physical inactivity may favor the development of MS. Insulin resistance is very commonly associated with abdominal obesity, but the molecular bases of the biological mechanisms relating insulin resistance and metabolic risk factors are not yet fully understood and do seem to be quite complex. (11) For that matter, the recent finding (9) that the stability of MS, particularly in adolescents, is low is striking and raises questions about the usefulness of the concept of MS in a clinical context.

According to the World Health Organization (WHO), (12, 13) MS is a complex metabolic disorder characterized by the association of impaired glucose tolerance / diabetes mellitus and/or insulin resistance, plus two or more of the following factors: SAH (values greater than 140/90mmHg); hypertriglyceridemia (plasma concentrations greater than 150mg/dl) and/or serum concentrations of high density lipoprotein (HDL-c) below 35mg/dl and 39mg/dL, in men and women, respectively; central/abdominal obesity or adiposity (determined by a waist-to-hip ratio greater than 0.90 for males and 0.85 for females) and/or Body Mass Index (BMI (a)) greater than 30kg/[m.sup.2]; microalbuminuria (rate of urinary albumin excretion greater than or equal to 20[micro]g/min or albumin-to-creatinine ratio greater than or equal to 30 mg/g).

Associations and clusterings of these factors have been known for decades, serving to clearly demonstrate that MS is a common condition, with a high prevalence worldwide and that it is still on the rise and occurring in populations of sedentary and obese individuals. (14) As a result, MS now appears as a serious public health problem, other than being a serious clinical problem.

The incidence of MS has increased at an alarming rate in recent years and it is estimated that over 50 million North-American individuals are affected by this chronic non-communicable disease (CNCD). (11) In 2001, the National Cholesterol Education Program (NCEP) (b), USA, reported that the diagnosis of MS is determined by the presence of three or more of the following conditions: abdominal obesity, (c) SAH, (d) impaired glucose tolerance, (e) hypertriglyceridemia, (f) low HDL-c concentrations. (g) For illustrative purposes, below is a list of what would be a full, typical repertoire of MS conditions.

* abdominal obesity (excessive fat accumulation in the abdomen);

* atherogenic dyslipidemia (blood fat and cholesterol disorders--hypertriglyceridemia, low HDL and high LDL levels--that cause accumulation of fatty plaques in artery walls);

* elevated blood pressure;

* insulin resistance or glucose intolerance;

* prothrombotic state (high fibrinogen or plasminogen activator inhibitor-1 levels in the bloodstream);

* proinflammatory state (elevated C-reactive protein levels in the bloodstream).

Representative table of the full repertoire of possible conditions, which do not always coexist all at once, in MS. Adapted from NCEP (2001)

According Lorenzo et al., (15) the definition proposed by the NCEP detects a greater number of individuals at risk for diabetes (48.7%) than the WHO definition (41.3%), since MS is a predictor of the development of diabetes mellitus, regardless of other risk factors.

Although it is relatively well-studied and accepted as a major health problem, there is still controversy as to whether MS is a true syndrome (h)--i.e., whether or not it is just a mixture of unrelated phenotypes. (14) It is known that MS cannot be used as an indicator of absolute risk, given that, per se, it does not have many of the factors that determine absolute risk--for example, age, sex, smoking and LDL levels. Still, individuals with MS are twice as likely to develop cardiovascular disease in the next five to ten years, and five times more likely to develop T2DM. Furthermore, individuals with the triad of conditions (obesity, T2DM and inflammation) usually manifest a prothrombotic and proinflammatory state. The association of MS with cardiovascular disease increases overall mortality by about 1.5 times.

The International Diabetes Federation (IDF) has recently published its definition of metabolic syndrome in children and adolescents. This panel suggests the following criteria: (1) for children between the ages of 6-10 years old, obesity (defined as waist circumference [greater than or equal to] 90th percentile), accompanied by other measurements as indicated by family history; (2) for children and adolescents aged 10-16 years, obesity (defined as waist circumference [greater than or equal to] 90th percentile), followed by the adult criteria for triglycerides, HDL-C, blood pressure, and glucose; (3) for youths [greater than or equal to] 16 years of age, the panel recommends using the existing IDF criteria for adults. This definition is based on waist circumference percentiles and is standard across all age groups considered.

Using the ATP III criteria defined by the NCEP and the WHO, studies were carried out in the mid-2000s, in different North-American countries, with the following results, which can be compared: in U.S. schools, with 1,513 adolescents, the prevalences of MS of 4.2% and 8.4%, respectively, were found; (16) in 965 Mexican children and adolescents, the percentages of 6.5% in children and 4.5% in adolescents were found; (17) in Canada, in the evaluation of 2,244 children and adolescents, the prevalence of MS was slightly higher (11.5%). (18)

Although the body of knowledge about the prevalence of MS in other countries and in different age groups in the population (children, adolescents and adults) is quite relevant, it is known that the prevalence of MS in different populations is highly dependent on the criteria used for its definition and there are still no comprehensive studies, at least not with significant data, regarding this prevalence in the Brazilian population. Initial studies on the prevalence of MS differed greatly in their results due to the different criteria used and their focus on specific subgroups within the population. Moreover, it has been suggested that each population validates this definition according to local ethnic characteristics. (19)

International organizations such as the IDF (International Diabetes Federation), NHLBI (National Heart, Lung and Blood Institute, U.S.), AHA (American Heart Association), WHF (World Heart Federation), IAS (International Atherosclerosis Society), and IASO (International Association for the Study of Obesity) regularly publish consensus documents and statements on the subject (8, 9, 20) in order to update the scientific community on the latest relevant guidelines. The most recent document was published in 2009 in the journal Circulation (v. 120, p. 640-1645) and must be used as the gold standard in studies involving MS

The most recent document (9) is considered an international guideline and represents the latest step for a unified definition of MS. In it, the consensus is that an individual must present at least three of the five clinical criteria defined as components of MS to allow for such a diagnosis. The presence of any of these criteria is not mandatory. The cut-off values for each of the criteria were well defined, except for the waist circumference, which must be assessed by each country, respecting its ethnicity, nationality and regionalization.

The role of insulin resistance as a factor able to explain all the clinical aspects remains unclear, both from a pathogenic viewpoint and as a criterion for diagnosis. The causes of MS remain linked to the social, economic and cultural context of the population, especially in what relates to physical activity and eating habits.

Obesity as a risk factor for MS

Obesity, defined as increased adipose tissue mass, is usually associated with chronic systemic inflammation and confers high risk for cancer and cardiovascular and metabolic disorders. (21) Obesity is considered a global epidemic, and the World Health Organization (22, 23) describes it as multifactorial, originating either isolatedly or from the interaction of genetic, social, cultural, nutritional, metabolic and/or endocrine factors. According to Conway & Rene, (24) obesity is a complex disease with a multifaceted etiology and its own pathophysiology, comorbidities and disabling capabilities. In Brazil, the demographic, socioeconomic and epidemiological changes over time allowed for a transition in dietary patterns, with a gradual reduction of malnutrition and increase in obesity. (25)

Over the last decade, there has been a continuing increase in obesity and its comorbidity with MS, although, in fact, little is actually known about the rate of metabolic dysfunction in these cases. (26) Several factors have been implicated as biomarkers for MS, among which insulin, uric acid (26) and C-reactive protein (CRP), plus two other factors directly related to obesity due to their association with adipose tissue, namely adiponectin and leptin. (27, 28)

Obesity has been associated with insulin resistance (29) and is considered the main risk factor for the development of prediabetes and T2DM (30, 31) and also of coronary heart disease (CHD). (32) Most cases of MS occur in individuals with overweight, which, by itself, affects the sensitivity to insulin that, in turn, decreases by 40% when the subject has a body mass 35% to 40% above the desirable range. (33) The excess body fat leads to lipid accumulation in various tissues, notably adipose tissue, muscles, liver and pancreatic [beta]-cells, which seems to induce the biochemical changes occurring in the MS. (20)

Cellular and molecular bases of adipose tissue function and dysfunction

Knowing about the molecular events that regulate the differentiation of preadipocytes and mesenchymal stem cells into adipocytes (adipogenesis) is important for understanding the genesis of obesity. Obesity results from an increase in the size and number of adipocytes, and the balance between adipogenesis and adiposity helps determine the degree of obesity of an individual. (34) In obesity, several hormones and cytokines seem to play a critical role in maintaining a high body weight.

It is known that mature adipocytes secrete adipokines (i) or adipocytokines, whose production is much higher in obesity, contributing to the onset of peripheral insulin resistance. In MS, adipose tissue has been shown to function as a paracrine and endocrine organ, secreting several adipocytokines, such as adiponectin and leptin, (28) besides the classic proinflammatory cytokines (interleukin-6 or IL-6, and tumor necrosis factor, TNF-[alpha]), (27) as well as lipokine, resistin, omentin, lipocalin and fatty acid-binding proteins (A-FABP), among others. These adipocytokines are known to interact in a quite complex manner.

Adiponectin and leptin appear to be directly associated with obesity and insulin resistance. (27, 28) It should be mentioned that adiponectin and leptin appear to have opposite associations with regard to MS and CHD. (35) Adipocytes and adipose tissue macrophages produce interleukin-6 (IL-6) in excess, while tumor necrosis factor-alpha (TNF-[alpha]) expression is increased in the visceral fat of obese subjects and correlates positively with the degree of obesity and plasma insulin levels. (36) IL-6 and TNF-[alpha] mediate lipolysis indirectly and increase hepatic fatty acid synthesis, therefore increasing serum levels of fatty acids and triglycerides. (37) In turn, the inflammatory cascade triggered by these cytokines is further stimulated by hyperinsulinemia. (38) IL-6 and TNF-[alpha] also act directly on the insulin receptor in order to reduce its signaling and, thus, increase insulin resistance. (39) In brief, visceral adipose tissue, increased in MS patients, disturbs adipocytokine secretion and leads to a low-grade chronic inflammatory state, through the infiltration of macrophages in the adipose tissue. (43) This inflammatory state is associated with insulin resistance and atherosclerosis. (43, 44, 45)

To be more specific, it follows that adiponectin has anti-atherogenic, anti-diabetic, and anti-inflammatory properties, which reduce insulin resistance, by increasing insulin sensitivity in the liver. In muscle tissue, adiponectin increases glucose utilization and fatty acid oxidation, besides also increasing endothelial nitric oxide (NO) secretion and inhibiting monocyte adhesion and smooth muscle cell proliferation of the vascular wall. (45, 46, 47)

As for leptin, it is also a proinflammatory cytokine and appears to be important in the regular control of the amount of body fat. It is a peptide hormone, a product of the ob gene, that functions as an afferent signal in a negative feedback loop regulating the size of adipose tissue mass. (28) The leptin concentration, which is also a known satiety factor, (48) is proportional to the number and size of adipocytes. (49) Recently, it has been the subject of research to elucidate how obesity stimulates systemic inflammation through the action and connection of several cytokines, including the very own increased leptin (50) and decreased adiponectin. (45, 46, 47)

Still regarding leptin, recent studies have shown that insulin and leptin act as regulators of a type of protein called aquaglyceroporins, which allow the movement of water and other smaller solutes, in particular glycerol, across cell membranes. Glycerol is a metabolite acting in the control of lipid accumulation and the glucose homeostasis, with an important role as a substrate for hepatic gluconeogenesis, in pancreatic insulin secretion and in cardiac ATP production. Aquaglyceroporins (AQP3, AQP7, AQP9 and AQP10) comprise a subfamily of aquaporins. (50, 51) Through a metabolic pathway known by the acronym PI3K/Akt/mTOR (Phosphatidylinositol 3-Kinase/Akt/mammalian target of rapamycin), and considering that adipose tissue is a major source of glycerol via AQP7, (49, 53) it has been recently reported that aquaglyceroporins (in particular AQP3 and AQP7) may facilitate glycerol efflux from adipose tissue while reducing glycerol influx into hepatocytes via AQP9, thus preventing the excessive lipid accumulation and the subsequent aggravation of hyperglycemia in human obesity. (51, 52) As shown in Figure 1, taken from Rodriguez et al.'s paper, (51) these versatile and significant functions of the aquaglyceroporins reveal the unexpected and emerging roles of these glycerol channels.

Other adipokines recently reported (54, 55) are: vaspin, visfatin, apelin, omentin, fractalkine, acylation stimulating protein (ASP) and retinol-binding protein 4 (RBP4). The role--sometimes beneficial, sometimes detrimental--of these adipokines in obesity and atherosclerosis has been extensively studied. Vaspin (an acronym for visceral adipose tissue-derived serine protease inhibitor) was identified as a member of the protein family of serine protease inhibitors, and may have anti-atherogenic effects through its insulin-sensitizing properties.

Similarly, visfatin also has these properties, but it seems to destabilize atherosclerotic plaques, which is a detrimental effect. Apelin, via inhibition of food intake and increases in physical activity and body temperature, may promote weight loss, resulting in a beneficial anti-atherogenic effect, which is associated with other positive effects on vasodilation and blood pressure. Considering its increased levels in atherosclerotic subjects, RBP4 may be a valuable biomarker. Also, ASP, often increased in obesity and MS, may contribute to efficient lipid storage, and decreasing or blocking it may provide a potential anti-obesity target.

As for omentin-1, the most common isoform, it has been identified as a new adipokine predominantly secreted by visceral stromal vascular cells, although it is not exactly produced by adipocytes.(55) In vitro experiments have shown that treatment with recombinant omentin-1 enhances insulin-stimulated glucose uptake in subcutaneous and omental human adipocytes while increasing the phosphorylation of Akt/PKB. Studies with human patients with T1DM showed a decrease in plasma omentin-1 levels, which are not affected by glucose intake. Furthermore, the plasma concentration and gene expression of omentin in visceral adipose tissue appear to decrease in obesity.

Visceral adipose tissue and adipokines

Numerous clinical and experimental studies, especially over the last decade, have focused on visceral adipose tissue and abdominal obesity. (45, 46) Abdominal fat is composed of subcutaneous fat and visceral fat, and, depending on the predominant fat, is classified as subcutaneous or visceral abdominal obesity, with the latter posing the highest risk for health. As reviewed, (56) omental or visceral adipose tissue (VAT) is the most active, i.e., more sensitive to lipolysis, via catecholamines and [beta]-adrenoreceptors, and more insulin-resistant, releasing a higher concentration of free fatty acids (FFA) directly into the portal vein. In addition, VAT secretes the highest concentrations of adipokines linked to pro-inflammatory processes, such as resistin, angiotensin I, plasminogen activator inhibitor-1 (PAI-1), PCR, IL-6, followed by subcutaneous abdominal adipose tissue (SAAT) and subcutaneous femoral-gluteal adipose tissue (SFGAT).

Regarding specific body fat stores, two- to three-fold expressions of resistin, one of the aforementioned adipokines, are found in visceral adipose tissue, followed by subcutaneous abdominal tissue and subcutaneous gluteal-femoral adipose tissue, and an increase in resistin expression can be an important link between abdominal obesity and T2DM. Besides, its expression is three times higher in preadipocytes than in mature adipocytes, and it also functions as a potential regulator of adipogenesis. (57)

Waist circumference is a recommended measurement for representing an anthropometric index representative of intra-abdominal fat and for being simple and reproducible. (58) This index is obtained by measuring halfway between the iliac crest and the lower costal border (Brazilian Society of Cardiology, 2005). For abdominal waist circumferences between 80 and 88 cm and between 94 and 102 cm in women and men, respectively, more frequent monitoring of risk factors for coronary heart diseases is recommended. (58)

It is known that adipokines can act as a link between visceral adiposity and atherosclerosis. (34) In visceral fat stores, turnover is faster than in other areas, which increases concentrations of PAI-1, inflammatory cytokines and non-esterified fatty acids (NEFA, according to the trilingual and structured vocabulary DeCS--Health Sciences Descriptors) in the portal system. The increased release of NEFA from adipose tissue stimulates gluconeogenesis, inhibits hepatic insulin clearance and causes accumulation of triglycerides in the liver and muscles, resulting in hyperglycemia and consequent hyperinsulinemia. Thus, the accumulation of fat in muscles leads to insulin resistance, whereas in the liver it promotes atherogenic dyslipidemia. (33, 59)

Final remarks

MS has shown a high global prevalence, occurring in groups of sedentary and obese individuals. The knowledge of the molecular bases that regulate inflammation, obesity and its comorbidities may provide new therapeutic approaches in the treatment or prevention of these pathologies.

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Received on: Aug. 09, 2012

Revised on: Nov. 10, 2012

Accepted on: Jan. 14, 2013

Ana Paula Moreira Bezerra (1)

Diana Magalhaes de Oliveira (2)

(1) Nutritionist, Master of Science in Nutrition and Health, Universidade Estadual do Ceara. Fortaleza, CE, Brazil.

(2) Associate Professor at Universidade Estadual do Ceara. Graduate Studies Program in Biotechnology by the Northeast Biotechnology Network and Master of Sciences Program in Nutrition and Health. Fortaleza, CE, Brazil.

Correspondencia/Correspondence

Diana Magalhaes de Oliveira

E-mail: diana.magalhaes@uece.br

(a) BMI = body mass in kilograms (Kg) divided by height in meters squared.

(b) NCEP, The National Cholesterol Education Program, created in 1985 by the National Heart, Lung, and Blood Institute (NHLBI) of the United States, aims at offering continuing education to professionals and the general public about the benefits of lowering cholesterol levels as a way to reduce the risks for coronary heart diseases.

(c) Abdominal obesity is determined by waist circumference values greater than 102 cm and 88 cm, in men and women, respectively.

(d) Arterial hypertension is defined by blood pressure levels equal to or greater than 130/85mmHg. e Fasting glucose between 110 and 125mg/dl.

(f) Hypertriglyceridemia is determined by values equal to or greater than 150mg/dl. g HDL-c: rates below 40mg/dl for men and 50mg/dl for women.

(h) A syndrome is simply a cluster of factors that appear together more often than they would naturally occur at random, the reason for such being regarded as either uncertain or multifactorial. MS meets this criterion for inclusion as a syndrome.

(i) Proinflammatory cytokines have widespread metabolic effects throughout the body, such as metabolic alterations in proteins, fats and trace elements, besides changes in hepatic protein synthesis. (40) Cytokines are defined as soluble proteins, synthesized by immune cells or not, mediating intracellular communication by transmitting information to target cells via interactions with specific receptors. Many cytokines have physiological activities other than those originally discovered. (41) Currently, the most accepted term to describe a protein that is secreted (and synthesized) by adipose tissue, whether or not it is a cytokine,42 is adipokine.

Quando Gerald Reaven, no final da decada de 1980, introduziu o conceito de sindrome metabolica (SM), esta se tornou topico de intensa discussao cientifica. A predisposicao genetica, a alimentacao inadequada e a inatividade fisica estao entre os principais fatores que contribuem para o surgimento da SM, cuja prevencao primaria e um desafio mundial contemporaneo. Embora a patogenese da SM nao esteja completamente elucidada, seus diferentes componentes estao possivelmente associados a resistencia a insulina. Na SM, ocorre uma provavel interacao dos fatores geneticos, metabolicos e ambientais, incluindo a dieta. O papel dos fatores dieteticos na presenca e no desenvolvimento da SM nao esta estabelecido de forma definitiva. Aspectos alimentares e nutricionais presentes na vida moderna, particularmente associados aos habitos alimentares inadequados e ao sedentarismo, desempenham expressivo papel na genese da obesidade, representando cadeia de causalidade de facil observacao, mas de dificil intervencao. Nesse sentido, esta revisao trata do estado da arte e das circunstancias que caracterizam a SM, evidenciando o conhecimento dos eventos moleculares (genes e proteinas) que regulam a adipogenese e sao importantes para o entendimento da obesidade como fator de risco da SM.

Palavras-chave: Sindrome X metabolico (SM). Obesidade. Genes reguladores. Adipogenia.

Introducao

Esta revisao objetiva apresentar e discutir estudos que caracterizam a sindrome metabolica (SM) e sua relacao com a obesidade. Trabalhos que abordam pontos de vista fisico, clinico, bioquimico e genetico dessa sindrome sao analisados, evidenciando suas bases moleculares, que vem ultimamente sendo desvendadas e dissecadas, a fim de melhor entender a adipogenese e a obesidade.

Em humanos adultos, o acumulo de multiplos fatores de risco cardiovascular ja era observado desde o inicio do seculo XX. (1, 2) Mais recentemente, porem, acumulos similares de certos fatores cardiacos receberam renovada atencao e termos como o quarteto mortal, (3) a sindrome de resistencia a insulina, (4) a Sindrome Metabolica (SM), (5) sindrome X, (6) ou ainda sindrome plurimetabolica, foram propostos com o intuito de descrever a conexao entre obesidade, resistencia a insulina, hipertensao arterial sistemica (HAS), dislipidemia, diabetes mellitus tipo 2 (DMT2), e doenca cardiovascular aterosclerotica (DCA). Pode-se dizer, entao, que a definicao dessa sindrome varia em termos de quais indicadores se apresentam e dos pontos de corte usados. (2)

Ha evidencias recentes, porem controversas, (7) com informacoes substanciais sobre obesidade infantil em associacao com resistencia a insulina, inflamacao e outros fatores de risco e seu papel coletivo para o risco aumentado de DCA e DMT2. A constelacao desses fatores de risco cardiovascular inter-relacionados em adultos veio a ser conhecida por sindrome metabolica (SM), uma denominacao que se mostra util tanto nos contextos clinicos quanto de pesquisa (2) e que recebeu recente atualizacao consensual de diretrizes mundiais para seu estudo, diagnostico e prevencao. (8, 9) A SM tem sido caracterizada, portanto, pela ocorrencia de disturbios complexos representados por um conjunto de fatores de risco cardiovascular, usualmente relacionados a deposicao central de gordura e resistencia a insulina. (10)

Outras condicoes associadas com a SM incluem inatividade fisica, envelhecimento, desequilibrio hormonal e predisposicao genetica. Alguns individuos sao geneticamente suscetiveis a resistencia a insulina. No entanto, fatores como excesso de gordura corporal e inatividade fisica podem favorecer o desenvolvimento da SM. E muito comum a associacao de resistencia a insulina com obesidade abdominal, mas as bases moleculares dos mecanismos biologicos entre resistencia a insulina e fatores de risco metabolico nao estao ainda totalmente esclarecidos e parecem ser realmente bastante complexos. (11) Chama a atencao, inclusive, o fato recem-levantado (9) de que a estabilidade da SM, especialmente em adolescentes, e baixa, o que suscita questoes sobre a utilidade do conceito de SM num contexto clinico.

De acordo com a Organizacao Mundial de Saude (OMS), (12, 13) a SM e um disturbio metabolico complexo que se caracteriza pela associacao de tolerancia a glicose prejudicada/diabetes mellitus e/ou resistencia insulinica, alem de dois ou mais dos seguintes fatores: HAS (valores superiores a 140/90mmHg); hipertrigliceridemia (concentracoes plasmaticas maiores que 150mg/dl) e/ou concentracoes sericas de lipoproteina de alta densidade (HDL-c) inferiores a 35mg/dl e 39mg/dl, em homens e mulheres, respectivamente; obesidade ou adiposidade central/abdominal (definida por relacao cintura-quadril superior a 0,90 para o sexo masculino e 0,85 para o feminino) e/ou Indice de Massa Corporal (IMC (a)) maior que 30kg/[m.sup.2]; microalbuminuria (taxa de excrecao urinaria de albumina maior ou igual a 20[micro]g/min ou razao albumina: creatinina maior ou igual a 30mg/g).

As associacoes e agrupamentos desses fatores sao conhecidos ha decadas, o que serviu para demonstrar claramente que a SM e comum, com alta prevalencia mundial, e continua crescendo e ocorrendo nos grupos populacionais de sedentarios e obesos. (14) Resultado disso, a SM agora surge como grave problema de saude publica, alem de continuar um grave problema clinico.

A incidencia de SM tem crescido assustadoramente nos ultimos anos e estima-se que mais de 50 milhoes de norte-americanos sejam acometidos por essa doenca cronica nao-transmissivel (DCNT). (11) Em 2001, o National Cholesterol Education Program (NCEP (b)), EUA, descreveu que o diagnostico de SM e determinado pela presenca de tres ou mais das seguintes afeccoes: obesidade abdominal (c), HAS (d), tolerancia a glicose prejudicada (e), hipertrigliceridemia (f), baixas concentracoes de HDL-c (g). Ilustrativamente, a listagem abaixo representaria um repertorio completo tipico de SM.

* obesidade abdominal (excessivo acumulo de gordura no abdomen);

* dislipidemia aterogenica (desordens de gordura sanguinea e colesterol--hipertrigliceridemia, baixo HDL e alto LDL--que provocam acumulo de placas gordurosas na parede das arterias);

* elevada pressao arterial;

* resistencia a insulina ou intolerancia a glicose;

* estado pro-trombotico (elevados niveis de fibrinogenio ou inibidor do ativador de plasminogenio-1 na corrente sanguinea);

* estado pro-inflamatorio (elevados niveis de proteina C-reativa na corrente sanguinea).

Quadro representativo do repertorio completo de condicoes possiveis, nem sempre todas coexistindo, na SM. Adaptado a partir de NCEP (2001)

Segundo Lorenzo et al., (15) a definicao do NCEP detecta maior numero de individuos em risco de diabetes (48,7%) do que a definicao da OMS (41,3%), uma vez que a SM constitui fator preditivo de desenvolvimento de diabetes mellitus, independentemente de outros fatores de risco.

Apesar de ser relativamente bem estudada e aceita como importante problema de saude, alguma controversia ainda persiste quanto a ser a SM uma verdadeira sindrome (h) ou nao--isto e, se ela seria apenas uma mistura de fenotipos nao-relacionados. (14) Sabe-se que a SM nao pode ser usada como indicador absoluto de risco, uma vez que ela nao contem per se muitos dos fatores que determinam o risco absoluto--por exemplo, idade, sexo, fumo e niveis de LDL. Ainda assim, os individuos com SM apresentam duas vezes mais riscos de desenvolver doenca cardiovascular nos proximos cinco a dez anos, e cinco vezes mais chances de desenvolver DMT2. Alem disso, os individuos com a triade (obesidade, DMT2 e inflamacao) geralmente apresentam um estado pro-trombotico e pro-inflamatorio. A associacao da SM com a doenca cardiovascular aumenta a mortalidade geral em cerca de 1,5 vez.

A Federacao Internacional de Diabetes (FID) publicou recentemente sua definicao de SM em criancas e adolescentes. Esse painel recomenda os seguintes criterios: (1) para criancas de 6-10 anos de idade, a obesidade (definida como circunferencia abdominal [greater than or equal to] percentil 90), acompanhada por outras medidas, conforme indicadas pelo historico familiar; (2) para a idade entre 10-16 anos, a obesidade (definida como circunferencia abdominal [greater than or equal to] percentil 90), seguida pelos criterios de adultos para trigliceridios, HDL-c, pressao arterial, e glicose; (3) Para jovens [greater than or equal to] 16 anos, o painel recomenda usar os mesmos criterios da FID para adultos. Essa definicao se baseia em percentis de circunferencia abdominal e e padrao para todas as faixas etarias previstas.

Usando os criterios do ATP III do NCEP e da OMS, estudos foram feitos, em meados da decada de 2000, em diferentes paises norte-americanos, com os seguintes resultados, que podem ser comparados: em escolas dos EUA, com 1.513 adolescentes, encontraram-se prevalencias de SM de 4,2% e 8,4%, respectivamente; (16) em 965 criancas e adolescentes mexicanos, encontraram-se os percentuais de 6,5% nas criancas e nos adolescentes, 4,5%; (17) no Canada, avaliando 2.244 criancas e adolescentes, a prevalencia de SM foi levemente superior (11.5%). (18)

Apesar de ser bastante relevante o conhecimento sobre a prevalencia da SM em outros paises e em diferentes faixas etarias da populacao (criancas, adolescentes e adultos), sabe-se que a prevalencia da SM nas diferentes populacoes depende muito dos criterios utilizados para sua definicao e ainda nao ha estudos abrangentes, pelo menos nao com dados significativos, sobre essa prevalencia na populacao brasileira. Os estudos iniciais de prevalencia da SM diferiram muito nos seus resultados, devido aos diversos criterios utilizados e porque selecionaram subgrupos especificos da populacao. Alem disso, tem-se sugerido que cada populacao tenha essa definicao validada de acordo com suas caracteristicas etnicas locais. (19)

Entidades internacionais como FID (Federacao Internacional de Diabetes), NHLBI (Instituto Nacional de Coracao, Pulmoes e Sangue, dos EUA), AHA (Associacao Americana do Coracao), WHF (Federacao Mundial do Coracao), IAS (Sociedade Internacional de Arteriosclerose) e IASO (Associacao Internacional para Estudos da Obesidade) costumam divulgar documentos e declaracoes de consenso sobre o assunto (8, 9, 20) para atualizar a comunidade cientifica sobre as mais recentes diretrizes pertinentes. O documento mais recente foi publicado em 2009 no periodico Circulation (v. 120, p. 640-1645) e deve ser utilizado como padrao-ouro nos trabalhos com SM.

O documento mais recente (9) e considerado uma diretriz internacional e representa o passo mais atual para a definicao unificada da SM. Nele, e consenso que o individuo necessita apresentar, pelo menos, tres dos cinco criterios clinicos definidos como componentes da SM para que seja possivel firmar tal diagnostico. A presenca de qualquer um desses criterios nao e obrigatoria. Os pontos de corte de cada um dos criterios foram bem definidos, exceto para os valores da circunferencia abdominal, que devem ser avaliados por cada pais, respeitando sua etnia, nacionalidade e regionalizacao.

O papel da resistencia a insulina como fator capaz de explicar todos os aspectos clinicos permanece ainda obscuro, tanto do ponto de vista da patogenese, como para um criterio diagnostico. As causas da SM permanecem vinculadas ao contexto social, economico e cultural da populacao, sobretudo naquilo que se relaciona a atividade fisica e alimentacao.

Obesidade como fator de risco para SM

A obesidade, definida como massa tecidual adiposa aumentada, geralmente se associa com inflamacao cronica sistemica, e confere altos riscos para cancer e desordens cardiovasculares e metabolicas. (21) A obesidade e considerada uma epidemia mundial, e a Organizacao Mundial da Saude (22, 23) a define como multifatorial, originando-se isoladamente ou na intercao de fatores geneticos, sociais, culturais, nutricionais, metabolicos e/ou endocrinos. Segundo Conway & Rene, (24) a obesidade e uma doenca complexa de etiologia multifacetada, com sua propria fisiopatologia, comorbidades e capacidades desabilitantes. No Brasil, as mudancas demograficas, socioeconomicas e epidemiologicas ao longo do tempo permitiram uma transicao nos padroes nutricionais, com a diminuicao progressiva da desnutricao e o aumento da obesidade. (25)

Ao longo da ultima decada, tem havido crescente aumento da obesidade e comorbididade com a SM, embora pouco ainda se saiba realmente sobre a taxa de disfuncao metabolica nesses casos. (26) Varios fatores tem sido implicados como biomarcadores da SM, dentre os quais a insulina, o acido urico (26) e a proteina C-reativa (PCR), alem de dois fatores diretamente ligados a obesidade por associacao ao tecido adiposo, a adiponectina e a leptina. (27, 28)

A obesidade tem sido associada com resistencia a insulina (29) e e tida como o principal fator de risco para o desenvolvimento da pre-diabetes e do DMT2 (30, 31) e tambem a doenca arterial coronariana (DAC). (32) A maioria dos casos de SM ocorre em individuos com excesso de peso, o que, por si so, prejudica a sensibilidade a insulina, que diminui em ate 40% quando o individuo apresenta massa corporal maior que 35% a 40% da ideal. (33) O excesso de gordura corporal leva ao acumulo de lipideos nos tecidos, notadamente no tecido adiposo, musculos, figado e celulas [beta] pancreaticas, o que parece induzir as alteracoes bioquimicas ocorridas na SM. (20)

Bases celulares e moleculares da funcao e disfuncao adiposa

O conhecimento dos eventos moleculares que regulam a diferenciacao dos pre-adipocitos e de celulas-tronco mesenquimais em adipocitos (adipogenese) e importante para o entendimento da genese da obesidade. A obesidade resulta do aumento no tamanho e no numero de adipocitos, sendo que o balanco entre adipogenese e adiposidade ajuda a determinar o grau de obesidade do individuo. (34) Na obesidade, varios hormonios e citocinas parecem ter papel fundamental na manutencao do alto peso corporeo.

Sabe-se que os adipocitos maduros secretam adipocinas (i) ou adipocitocinas, cuja producao e bem maior na obesidade, o que contribui para o estabelecimento de resistencia periferica a insulina. Na SM, o tecido adiposo parece funcionar como um orgao paracrino e endocrino, secretando varias adipocitocinas, tais como a adiponectina e a leptina, (28) alem das citocinas pro-inflamatorias classicas (interleucina-6 ou IL-6, e o fator de necrose tumoral, TNF-[alpha]), (27) assim como lipocina, resistina, omentina, lipocalina e as proteinas adipocitarias de ligacao a acido graxo ou fatty acid binding proteins (A-FABP), dentre outras. Tais adipocitocinas sao conhecidas por interagirem de forma bastante complexa.

A adiponectina e a leptina parecem estar diretamente associadas com obesidade e resistencia a insulina. (27, 28) Deve-se mencionar o fato de que a adiponectina e a leptina parecem ter associacoes opostas com relacao a SM e DAC. (35) Os adipocitos e macrofagos do tecido adiposo produzem Interleucina 6 (IL-6) em execesso, enquanto a expressao de fator necrosante tumoral alfa (TNF-[alpha]) esta aumentada na gordura visceral de obesos e se correlaciona positivamente com o grau de obesidade e com os niveis de insulina plasmatica. (36) IL-6 e TNF-[alpha] medeiam indiretamente a lipolise e aumentam a sintese hepatica de acidos graxos, de modo tal que aumentam os niveis sericos dos acidos graxos e triglicerides. (37) A cascata inflamatoria disparada por essas citocinas e, por sua vez, ainda mais estimulada pela hiperinsulinemia. (38) IL-6 e TNF-[alpha] tambem atuam diretamente no receptor de insulina para diminuir sua sinalizacao e, entao, aumentar a resistencia a insulina. (39) Pode-se resumir explicando que o tecido adiposo visceral, aumentado na SM, perturba a secrecao de adipocitocinas e leva a um estado inflamatorio cronico de baixa intensidade, pela infiltracao de macrofagos no tecido adiposo. (43) Esse estado inflamatorio se associa com a resistencia a insulina e a aterosclerose. (43, 44, 45)

Para detalhar melhor, tem-se que a adiponectina possui propriedades antiaterogenicas, antidiabeticas e anti-inflamatorias, atenuando a resistencia a insulina pelo aumento da sensibilidade insulinica no figado. No tecido muscular, a adiponectina aumenta a utilizacao de glicose e a oxidacao de acidos graxos, alem de aumentar a secrecao de oxido nitrico (NO) endotelial e de inibir a adesao de monocitos e a proliferacao de celulas da musculatura lisa da parede vascular. (45, 46, 47)

Quanto a leptina, ela tambem e uma citocina pro-inflamatoria e parece ser importante na regulacao perene da quantidade de gordura corporal. Ela e um hormonio peptideo, produto do gene ob, que age como sinal aferente num loop de feedback negativo na regulacao do tamanho da massa de tecido adiposo. (28) A concentracao de leptina, que tambem e um fator conhecido de saciedade, (48) e proporcional ao numero e tamanho dos adipocitos. (49) Ela tem sido alvo recente de pesquisas para se esclarecer como a obesidade estimula a inflamacao sistemica atraves da acao e conexao de diversas citocinas, incluindo a propria leptina aumentada (50) e a adiponectina diminuida. (45, 46, 47)

Ainda sobre a leptina, recentes estudos demonstraram que a insulina e a leptina agem como reguladoras de um tipo de proteinas, chamadas aquagliceroporinas, que permitem o movimento de agua e de outros solutos menores, em especial o glicerol, atraves das membranas celulares. O glicerol e um metabolito atuante no controle do acumulo lipidico e na homeostase da glicose, importante como substrato para a gliconeogenese hepatica, para secrecao pancreatica de insulina e para a producao cardiaca de ATP. As aquagliceroporinas (AQP3, AQP7, AQP9 e AQP10) compreendem uma subfamilia das aquaporinas. (50, 51) Atraves de uma via metabolica conhecida pela sigla PI3K/Akt/mTOR (Phosphatidylinositol 3-Kinase/Akt/mammalian target of rapamycin), e considerando que o tecido adiposo constitui uma fonte primordial de glicerol via AQP7, (49, 53) relatos mais recentes tem evidenciado que as aquagliceroporinas (em particular AQP3 e AQP7) parecem facilitar o efluxo de glicerol a partir do tecido adiposo, ao mesmo tempo em que podem reduzir o influxo de glicerol para o interior dos hepatocitos via AQP9, prevenindo o excesso de lipidios e o subsequente agravamento da hiperglicemia na obesidade humana. (51, 52) Conforme ilustra a figura 1, extraida do artigo de Rodriguez et al., (51) pode-se constatar que funcoes tao versateis e relevantes das aquagliceroporinas deixam transparecer os papeis inesperados e emergentes desses canais de glicerol.

Outras adipocinas recem-reportadas (54, 55) sao: vaspina, visfatina, apelina, omentina, fractalquina, proteina estimulante de acilacao (acylation stimulating protein, ASP) e proteina de ligacao ao retinol (retinol-bindingprotein 4, RBP4). O papel, ora benefico ora deleterio, dessas adipocinas na obesidade e aterosclerose, tem sido bastante estudado. A vaspina (acronimo para visceral adipose tissue-derived serine protease inhibitor) foi identificada como membro da familia proteica de inibidores serino-protease, podendo ter efeitos antiaterogenicos atraves de suas propriedades sensibilizadoras de insulina.

Do mesmo modo, a visfatina tambem possui essas propriedades, mas ela parece desestabilizar placas ateromatosas, o que vem a ser um efeito deleterio. A apelina, via inibicao do consumo alimentar e aumento na atividade fisica e temperatura corporal, pode promover perda de peso, resultando em efeito benefico antiaterogenico, que se associa a outros efeitos positivos na vasodilatacao e pressao sanguinea. Considerando os niveis elevados de RBP4 em individuos ateroscleroticos, essa proteina pode constituir um bom biomarcador. Outrossim, a ASP, geralmente aumentada na obesidade e SM, pode contribuir no armazenamento eficiente de lipidios, podendo o decrescimo ou bloqueio dessa proteina fornecer um alvo antiobesidade em potencial.

Quanto a omentina-1, a isoforma mais comum, foi identificada como uma nova adipocina predominantemente secretada pelas celulas vasculares do estroma visceral, embora nao seja produzida exatamente pelos adipocitos. (55) Experimentos in vitro revelaram que o tratamento com omentina-1 recombinante acentua a captacao de glicose mediada por insulina em adipocitos humanos subcutaneos e do omento, ao mesmo tempo em que aumenta a fosforilacao de Akt/PKB. Ja estudos com pacientes humanos portadores de T1DM demonstraram o decrescimo da concentracao plasmatica de omentina-1 nao afetada por ingestao de glicose. Ademais, a concentracao plasmatica e a expressao genica de omentina no tecido adiposo visceral parecem decrescer na obesidade.

Tecido adiposo visceral e adipocinas

Inumeros estudos clinicos e experimentais, especialmente na ultima decada, enfocaram o tecido adiposo visceral e a obesidade abdominal. (45, 46) A gordura abdominal e composta por gordura subcutanea e visceral, a qual, dependendo do tipo predominante de gordura, e classificada como obesidade abdominal subcutanea ou visceral, sendo esta a de maior risco para a saude. Conforme revisto, (56) o tecido adiposo visceral (TAV) ou omental e o mais ativo, ou seja, mais sensivel a lipolise, via catecolaminas e [beta]-adrenorreceptores, e mais resistente a acao da insulina, liberando maior concentracao de acidos graxos livres (AGL), diretamente na veia porta. Alem disso, o TAV secreta maiores concentracoes de adipocinas ligadas a processos pro-inflamatorios como resistina, angiotensina I, inibidor plasminogenio ativado 1 (PAI-1), RCP, IL-6, seguido do tecido adiposo subcutaneo abdominal (TASA) e do tecido adiposo subcutaneo gluteo-femural (TASG).

Em relacao aos depositos especificos de gordura corporal, expressoes duas a tres vezes maiores de resistina, uma das adipocinas ja citadas, sao encontradas no tecido adiposo visceral, seguido de subcutaneo abdominal e subcutaneo gluteo-femural, podendo o aumento da expressao de resistina ser um importante elo entre obesidade abdominal e DMT2. Alem disso, sua expressao e tres vezes maior nos pre-adipocitos quando comparada aos adipocitos maduros, funcionando tambem como potencial reguladora da adipogenese. (57)

A circunferencia abdominal e uma medida recomendada por representar um indice antropometrico representativo da gordura intra-abdominal e de afericao simples e reprodutivel. (58) A afericao desse indice se faz pela medida no meio da distancia entre a crista iliaca e o rebordo costal inferior (SBC, 2005). Para circunferencia de cintura abdominal entre 80-88 cm e 94-102 cm, respectivamente para mulheres e homens, recomenda-se monitorizacao mais frequente dos fatores de risco para doencas coronarianas. (58)

Sabe-se que as adipocinas podem atuar como um elo entre adiposidade visceral e aterosclerose. (34) Nos depositos viscerais de gordura, ha turnover mais acelerado que em outras regioes, elevando as concentracoes de PAI-1, citocinas inflamatorias e acidos graxos nao esterificados, segundo DECS (NEFA) no sistema porta. A maior liberacao de NEFA do tecido adiposo estimula a gliconeogenese, inibe a depuracao hepatica de insulina e provoca acumulo de triglicerides no figado e musculo, resultando em hiperglicemia e consequente hiperinsulinemia. Assim, o acumulo de gordura no musculo leva a resistencia insulinica, enquanto no figado, promove a dislipidemia aterogenica. (33, 59)

Consideracoes finais

A SM tem-se mostrado com alta prevalencia mundial e ocorrendo nos grupos de sendentarios e obesos. O conhecimento das bases moleculares que regulam a inflamacao, obesidade e suas comorbidades, pode proporcionar novas abordagens terapeuticas no tratamento ou prevencao destas patologias.

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Recebido: 09/8/2012

Revisado: 10/11/2013

Aprovado: 14/1/2013

Ana Paula Moreira Bezerra [1]

Diana Magalhaes de Oliveira [2]

[1] Nutricionista, Curso de Mestrado Academico em Nutricao e Saude, Universidade Estadual do Ceara. Fortaleza, CE, Brasil.

[2] Professora Adjunto da Universidade Estadual do Ceara. Programa de Pos-Graduacao em Biotecnologia da Rede Nordeste de Biotecnologia e Curso de Mestrado Academico em Nutricao e Saude. Fortaleza, CE, Brasil.

Correspondencia/Correspondence

Diana Magalhaes de Oliveira

E-mail: diana.magalhaes@uece.br

(a) IMC = divisao da massa corporal em quilogramas (Kg) pela estatura em metros ao quadrado.

(b) O NCEP, The National Cholesterol Education Program, criado em 1985 pelo National Heart, Lung, and Blood Institute (NHLBI) dos Estados Unidos, tem por objetivo a educacao continuada de profissionais e do publico em geral acerca dos beneficios da reducao dos niveis de colesterol como maneira de reduzir os riscos das doencas coronarianas.

(c) Obesidade abdominal e determinada por valores de circunferencia de cintura superiores a 102 cm e 88cm, em homens e mulheres, respectivamente.

(d) Hipertensao arterial e definida por niveis pressoricos iguais ou maiores que 130/85mmHg.

(e) Glicemia de jejum entre 110 e 125mg/dl.

(f) Hipertrigliceridemia considerada com valores iguais ou superiores a 150mg/dl.

(g) HDL-c: taxas inferiores a 40mg/dl para homens e 50mg/dl para mulheres.

(h) Uma sindrome e simplesmente um agrupamento de fatores que aparecem frequentemente mais juntos do que naturalmente ocorreriam ao acaso e cuja causa para isso pode ser tida como incerta ou multifatorial. A SM atende esse criterio para inclusao como sindrome.

(i) As citocinas pro-inflamatorias possuem efeitos metabolicos de longo alcance por todo o corpo, como alteracoes metabolicas das proteinas,

gorduras e oligoelementos, alem de alteracoes na sintese hepatica das proteinas. (40) As citocinas sao definidas como proteinas soluveis sintetizadas por celulas imunes ou nao, que medeiam a comunicacao intracelular por transmitirem informacoes a celulas-alvo, via interacoes com receptores especificos. Muitas citocinas possuem atividades fisiologicas muito alem daquelas originalmente descobertas. (41) Atualmente, o termo mais aceito para descrever uma proteina que e secretada (e sintetizada) pelo tecido adiposo, sendo esta proteina uma citocina ou nao, (42) e adipocina.
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Title Annotation:articulo en ingles
Author:Bezerra, Ana Paula Moreira; de Oliveira, Diana Magalhaes
Publication:Demetra: Food, Nutrition & Health
Date:Apr 1, 2013
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