腹型肥胖的研究进展

近年来腹型肥胖作为代谢综合征最重要的特征得到了广泛关注."脂质异位沉积"学说提出腹部皮下脂肪与内脏脂肪一样,在促进胰岛素抵抗形成的过程中发挥关键作用,同时也是导致心血管代谢风险的重要因素,而并非仪表现为既往所认为的机体保护作用.提示无论腹部皮下脂肪还是内脏脂肪堆积引起的腰围增加都应当得到足够的重视,也进一步支持将腰围作为代谢综合征工作定义中肥胖的诊断标准.腹型肥胖的治疗基础仍是生活方式干预,而体液因子、胃肠道激素及棕色脂肪研究的开展为腹型肥胖提供了新的治疗方向.     

Adipocytokines and liver disease

Adipose tissue is a massive source of bioactive substances known as adipocytokines, including tumor necrosis factor (TNF)-α, resistin, leptin, and adiponectin. Recent advances in medical research view obesity as a chronic low-grade inflammatory state. Hypertrophied adipocytes in obesity release chemokines that induce macrophage accumulation in adipose tissue. Accumulated macrophages in obese adipose tissue produce proinflammatory cytokines and nitric oxide, and these inflammatory changes induce adipocytokine dysregulation. The latter is characterized by a decrease in insulinsensitizing and anti-inflammatory adipocytokines, and an increase in proinflammatory adipocytokines. Adipocytokine dysregulation induces obesity-related metabolic disorders, the so-called metabolic syndrome. Metabolic syndrome is a cluster of metabolic abnormalities, including diabetes mellitus, hypertension, hyperlipidemia, and nonalcoholic steatohepatitis (NASH). Recent studies have revealed that obesity is an independent risk factor for chronic liver diseases, such as NASH, alcoholic liver disease, chronic hepatitis C, and hepatocellular carcinoma. A common mechanism underlying these hepatic clinical states is thought to be adipocytokine dysregulation. In this review, we discuss the association of adipocytokines, especially leptin, adiponectin, TNF-α, and resistin, with liver diseases.     

Adipose tissue dysfunction and the pathogenesis of metabolic syndrome

Metabolic syndrome is a growing research area. The underlying mechanisms of metabolic syndrome are still not very clear. Insulin resistance, obesity, inflammation and oxidative stress may play an important role in the pathogenesis of metabolic syndrome. The role of adipose tissue dysfunction is emphasized during the development of obesity. Adipose tissue is identified as a complex endocrine organ and its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. Chronic low-grade inflammation activated by the immune system in adipose tissue is a key contributing factor to type 2 diabetes mellitus and cardiovascular diseases. Visceral obesity results in cell autonomous impairment in insulin signaling that leads to insulin resistance. Chronic inflammation in adipose tissue has gained acceptance as a lead promoter of insulin resistance in obesity. Furthermore, obesity creates oxidative stress conditions in adipose tissue that not only correlates with insulin resistance but is also causative in its development. Oxidative stress may be a mechanistic link between several components of metabolic syndrome and cardiovascular diseases, through its role in inflammation and its ability to disrupt insulin-signaling. The study around adipose tissue dysfunction will help to understand the pathogenesis of metabolic syndrome and may bring effective therapy in treatment of metabolic syndrome related diseases. Therefore, this review mainly focuses on the roles of adipose tissue dysfunction in inflammation, insulin resistance, and oxidative stress in the pathogenesis of metabolic syndrome.     

Treatment of hypertension in metabolic syndrome: Implications of recent clinical trials

Metabolic syndrome represents a constellation of hypertension, abdominal obesity, impaired fasting glucose, and dyslipidemia, and it has been shown to be a risk factor for cardiovascular disease. The components of metabolic syndrome are rapidly emerging as epidemics of the twenty-first century, and reduction of these underlying causes, such as obesity, physical inactivity, and atherogenic diet, is first-line therapy. Treatment of hypertension and other cardiometabolic risk factors of the syndrome is also required. Evidence demonstrates a relationship between hypertension, type 2 diabetes mellitus, and several vascular and metabolic abnormalities that are components of metabolic syndrome. Hypertension associated with metabolic syndrome has pathophysiologic characteristics that provide clinical challenges as well as opportunities for successful therapeutic interventions. This article reviews the treatment of hypertension as a metabolic and vascular disease and also opens a new paradigm for the treatment of metabolic syndrome, which affects nearly one quarter of the world’s population.     

Visceral fat as a determinant of fibrinolysis and hemostasis

An increased amount of deep abdominal visceral fat has generally been accepted as an important cardiovascular risk factor, and disturbances in hemostasis and fibrinolysis have been suggested to play a role. Fibrinogen and von Willebrand factor, representatives of the hemostatic system, and plasminogen activator inhibitor 1 (PAI-1), as the most important inhibitor of the fibrinolytic system, have been associated with visceral obesity, with the most convincing evidence found for the involvement of PAI-1. The association with fibrinogen and von Willebrand factor has been suggested to be merely a reflection of the association with inflammation and endothelial dysfunction. The fact that PAI-1 is secreted by adipose tissue has attracted much attention. The increase of PAI-1 in visceral obesity could be because visceral adipose tissue produces more PAI-1 compared with subcutaneous abdominal adipose tissue. The contribution of other cell types such as hepatocytes or endothelial cells is probably more important, with stimulation of PAI-1 production by different components of the metabolic syndrome. PAI-1 secretion by adipose tissue has been suggested to have a more local effect, playing a role in tissue remodeling during the development of obesity.     

An update on metabolic syndrome: Metabolic risk markers and adipokines in the development of metabolic syndrome

BackgroundMetabolic syndrome is a collection of physiological and biochemical abnormalities about 20–25% of adult population in developing countries is suffering from metabolic syndrome. Previous research demonstrated that adipose tissue plays an important role in energy regulation via endocrine, paracrine and autocrine signals as results of obesity due to accumulation of adipose tissue to excess that by time affects negatively both physical and psychological health and well being, it has been found that adipose tissues produces a variety of factors known as “adipokines” which play a key role in the development and progression of the disease and also hypothesized that adipokines are a possible link between obesity and the other risk components of the Metabolic syndrome. Many of the adipokines exert multiple actions in a variety of cellular processes leading to a complex array of abnormal characteristic of Metabolic syndrome. Abnormal production of these adipokines by expanded visceral fat during Adiposity contributes to a pro-inflammatory state. Increasing evidence suggests that aberrant production/release of adipokine from adipocyte i.e. adiponectin, leptin and resistin etc, may contribute to the health problems associated with Adiposity such as dyslipidemia, insulin resistance and atherosclerosis. This study conclusively have shown a significant role of adipokines secreted by adipose tissue and various metabolic risk markers play a important role in the development of Metabolic syndrome.     

Metabolic syndrome: its history,mechanisms, and limitations

In late twentieth century, Ruderman and Reaven showed that insulin resistance might be fundamental to metabolic syndrome (MetS) which means a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 2001, user-friendly National Cholesterol Education Program (NCEP) criteria of MetS were proposed. In 2005, the International Diabetes Federation (IDF) and the Examination Committee for Criteria of Metabolic Syndrome in Japan issued different criteria of MetS where abdominal obesity is a necessary component. In 2009, IDF, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity jointly adopted the revised NCEP criteria, where abdominal obesity is not a necessary component, as worldwide criteria of MetS. In 2010, WHO Expert Consultation warned that MetS is a concept that focuses attention on complex multifactorial health problems but has limited practical utility as a management tool. In animal studies, adipose tissue inflammation characterized by an increased number of crown-like structures in adipose tissue, rather than obesity per se, was shown to be a fundamental mechanism of metabolic derangements.     

Potential impact of Helicobacter pylori-related metabolic syndrome on upper and lower gastrointestinal tract oncogenesis

Both Helicobacter pylori infection and metabolic syndrome present significant global public health burdens. Metabolic syndrome is closely related to insulin resistance, the major underlying mechanism responsible for metabolic abnormalities, and Helicobacter pylori infection has been proposed to be a contributing factor. There is growing evidence for a potential association between Helicobacter pylori infection and insulin resistance, metabolic syndrome and related morbidity, including abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, all of which increase mortality related to cardio-cerebrovascular disease, neurodegenerative disorders, nonalcoholic fatty liver disease and malignancies. More specifically, insulin resistance, metabolic syndrome and hyperinsulinemia have been associated with upper and lower gastrointestinal tract oncogenesis. Apart from cardio-cerebrovascular, degenerative diseases and nonalcoholic fatty liver disease, a number of studies claim that Helicobacter pylori infection is implicated in metabolic syndrome-related Barrett's esophagus and esophageal adenocarcinoma development, gastric and duodenal ulcers and gastric oncogenesis as well as lower gastrointestinal tract oncogenesis. This review summarizes evidence on the potential impact of Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease-Barrett's esophagus-esophageal adenocarcinoma, gastric atrophy-intestinal metaplasia-dysplasia-gastric cancer and colorectal adenoma-dysplasia-colorectal cancer sequences. Helicobacter pylori eradication might inhibit these oncogenic processes, and thus further studies are warranted.     

Metabolic fatty liver diseases: hepatic consequences of the metabolic syndrome

Metabolic fatty liver diseases (Non Alcoholic Fatty Liver Diseases-NAFLD) are liver abnormalities (steatosis and steatohépatitis) commonly related to visceral obesity and to the metabolic syndrome. The pathogenesis of metabolic fatty liver diseases is most probably linked to the adipose tissue insulin resistance with a very high free fatty acids release, an abnormal secretion of factors produced by the adipose tissue (adipokines) and a low grade of chronic inflammation. The link between metabolic fatty liver diseases and the metabolic syndrome is further supported by epidemiological studies, as well as the frequently encountered cardio-vascular complications in both diseases. Changes in lifestyle with dietary restriction and increased physical activity are mandatory and similar for both conditions. Drugs such as thiazolidinediones, known to reduce insulin resistance and inflammation, still need further evaluation.     

Influence of metabolic syndrome on upper gastrointestinal disease

A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases.     

Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.     

Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk

There is currently substantial confusion between the conceptual definition of the metabolic syndrome and the clinical screening parameters and cut-off values proposed by various organizations (NCEP-ATP III, IDF, WHO, etc) to identify individuals with the metabolic syndrome. Although it is clear that in vivo insulin resistance is a key abnormality associated with an atherogenic, prothrombotic, and inflammatory profile which has been named by some the "metabolic syndrome" or by others "syndrome X" or "insulin resistance syndrome", it is more and more recognized that the most prevalent form of this constellation of metabolic abnormalities linked to insulin resistance is found in patients with abdominal obesity, especially with an excess of intra-abdominal or visceral adipose tissue. We have previously proposed that visceral obesity may represent a clinical intermediate phenotype reflecting the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink for the clearance and storage of the extra energy derived from dietary triglycerides, leading to ectopic fat deposition in visceral adipose depots, skeletal muscle, liver, heart, etc. Thus, visceral obesity may partly be a marker of a dysmetabolic state and partly a cause of the metabolic syndrome. Although waist circumference is a better marker of abdominal fat accumulation than the body mass index, an elevated waistline alone is not sufficient to diagnose visceral obesity and we have proposed that an elevated fasting triglyceride concentration could represent, when waist circumference is increased, a simple clinical marker of excess visceral/ectopic fat. Finally, a clinical diagnosis of visceral obesity, insulin resistance, or of the metabolic syndrome is not sufficient to assess global risk of cardiovascular disease. To achieve this goal, physicians should first pay attention to the classical risk factors while also considering the additional risk resulting from the presence of abdominal obesity and the metabolic syndrome, such global risk being defined as cardiometabolic risk.     

Clinical characteristics of metabolic syndrome in Korea,and its comparison with other Asian countries

Metabolic syndrome is referred to as syndrome X or insulin resistance syndrome, and is primarily composed of abdominal obesity, diabetes, glucose intolerance, dyslipidemia and high blood pressure. Asians have a lower frequency of obesity than Caucasians, but have an increasing tendency toward metabolic syndrome. Thus, metabolic syndrome poses a major challenge for public health professionals, and is set to become a social and economic problem in Asian populations. Most data on metabolic syndrome are based on studies from Western countries with only limited information derived from Asian populations. Recently, several studies were carried out on a large scale that represents the general Korean population. The prevalence of metabolic syndrome in Korean adults has varied depending on the study designs and different criteria, but shows a distinct increasing trend of metabolic syndrome driven by an increase in abdominal obesity and dyslipidemia. Given the rapid economic progression of Korea over the past 30 years along with a rise of the aged population, it is expected that the prevalence of metabolic syndrome will further increase. Therefore, a proactive strategy at the governmental level for metabolic syndrome prevention should be implemented, reducing abdominal obesity and dyslipidemia. Healthy dietary habits and regular exercise should be emphasized as a part of such a strategy.     

AIMing at metabolic syndrome. -Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM).-

Metabolic syndrome (MetS) is a cascade of metabolic diseases, starting with obesity and progressing to atherosclerosis, and is often fatal because of serious cardiovascular problems such as heart/brain infarction and hemorrhage. Accumulating evidence has revealed a critical involvement of inflammatory responses triggered by lesional macrophages in the pathogenesis of MetS. Importantly, we found that macrophages are associated with disease progression, not only in the induction of inflammation but also in the production of apoptosis inhibitor of macrophages (AIM), which we initially identified as a soluble factor expressed by macrophages. In atherosclerotic plaques, AIM is highly expressed by foam macrophages and inhibits apoptosis of these cells, which results in the accumulation of macrophages, causing inflammatory responses within the lesion, and ultimately disease progression. In adipose tissue, macrophage-derived AIM is incorporated into adipocytes through CD36-mediated endocytosis, thereby reducing the activity of cytosolic fatty acid synthase. This unique response stimulates lipolysis, resulting in a decrease in adipocyte size, which is physiologically relevant to the prevention of obesity. The lipolytic response also stimulates inflammation of adipocytes in association with the induction of metabolic disorders subsequent to obesity. Thus, AIM is involved in the progression of MetS in both an advancing and inhibitory fashion. Regulation of AIM could therefore be therapeutically applicable for MetS.     

饮酒与代谢综合征

代谢综合征是一组包括超重或腹型肥胖、高血糖、高血压、高甘油三酯及低高密度脂蛋白血症等的代谢紊乱症候群,也是多重心脑血管疾病危险因素聚集的表现。过去20年来的研究发现饮酒对体内多元代谢有着复杂影响,对代谢综合征具有保护和促进的双重矛盾效应。本文从饮酒与代谢综合征中各种组分的关系出发,分析饮酒对代谢综合征的利与弊。     

Contribution of CB1 blockade to the management of high-risk abdominal obesity

The worldwide increase in the prevalence of type 2 diabetes represents a tremendous challenge for our healthcare system, especially if we consider that this phenomenon is largely explained by the epidemic of obesity. However, despite the well-recognized increased morbidity and mortality associated with an elevated body weight, there is now more and more evidence highlighting that abdominal adipose tissue is the fat depot that conveys the greatest risk of metabolic complications. This cluster of metabolic abnormalities has been referred to as the metabolic syndrome and this condition is largely the consequence of abdominal obesity, especially when accompanied by a high accumulation of visceral adipose tissue. This cluster of metabolic complications has also been found to be predictive of a substantially increased risk of coronary heart disease beyond the presence of traditional risk factors. Moreover, a moderate weight loss in initially abdominally obese patients is associated with a selective mobilization of visceral adipose tissue, leading to improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes. The recent discovery of the endocannabinoid-CB1 receptor system and of its impact on the regulation of energy metabolism represents a significant advance, which will help physicians target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant therapy (the first developed CB1 blocker) could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its effects not only on energy balance but also on adipose tissue metabolism. For instance, the presence of CB1 receptors in adipose tissue and the recently reported effect of rimonabant on adiponectin production by adipose cells may represent a key factor responsible for the weight loss-independent effect of this CB1 blocker on cardiometabolic risk variables.     

Roles of skeletal muscle and peroxisome proliferator-activated receptors in the development and treatment of obesity

Metabolic disturbances associated with alterations in lipid metabolism, such as obesity, type 2 diabetes, and syndrome X, are becoming more and more prominent in Western societies. Despite extensive research in such pathologies and their molecular basis, we are still far from completely understanding how these metabolic perturbations are produced and interrelate and, consequently, how to treat them efficiently. The discovery that adipose tissue is, in fact, an endocrine tissue able to secrete active molecules related to lipid homeostasis--the adipokines--has dramatically changed our understanding of the molecular events that take place in such diseases. This knowledge has been further improved by the discovery of peroxisome proliferator-activated receptors and their ligands, at present commonly used for the clinical treatment of lipid disturbances. However, a key point remains to be solved, and that is the role of muscle lipid metabolism, notably because of the main role played by this tissue in the development of such pathologies. In addition, a reciprocal regulation between adipose tissue and skeletal muscle has been proposed. New discoveries on the role of peroxisome proliferator-activated receptor-delta in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders.     

Specialists Play a Vital Role in General Practitioners' Prescription Behavior: A Qualitative Study of Asthma Care in Japan

Background. The prevalence of obesity and asthma has been increasing during the last several decades. Obesity has been reported to be associated with asthma. Obesity, especially abdominal obesity, is the main component of the metabolic syndrome. Objectives. We thus hypothesized that metabolic syndrome is an important contributing factor for the development of asthma-like symptoms. Methods. The Korean Health and Genome Study started in 2001 as an ongoing population-based study of Korean adults 40 to 69 years of age. The prevalence of asthma-like symptoms in the previous 12 months was obtained by a questionnaire, and spirometric testing was conducted. Results. Among the 10,038 participants, the data from 9,942 individuals (4,716 men and 5,226 women) was available. Asthma-like symptoms (wheeze [p = 0.0006], resting dyspnea [p = 0.0062], and post-exercise dyspnea [p < 0.0001]) were increased in the subjects of the metabolic syndrome group. Subjects with asthma-like symptoms had a decreased lung function compared to subjects without asthma-like symptoms. Among the components of the metabolic syndrome, abdominal obesity and hypertension were the risk factors for asthma-like symptoms. Conclusions. Metabolic syndrome is associated with asthma-like symptoms. Among the components of metabolic syndrome, abdominal obesity and hypertension are the risk factors for asthma-like symptoms.     

The metabolic syndrome and inflammation: association or causation?

The aim of this editorial was to discuss evidence indicating a role for low-grade inflammation as a pathogenetic event of the metabolic syndrome. The metabolic syndrome has emerged as an important cluster of risk factors for atherosclerotic disease. Common features are central (abdominal) obesity, insulin resistance, hypertension, and dyslipidemia, namely high triglycerides and low high-density lipoprotein cholesterol. According to the clinical criteria developed by ATP III, it has been estimated that 1 out of 4 adults living in the United States merits the diagnosis. The presence of the metabolic syndrome is highly prognostic of future cardiovascular events. Chronic inflammation may represent a triggering factor in the origin of the metabolic syndrome: stimuli such as overnutrition, physical inactivity, and ageing would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. Alternatively, resistance to the anti-inflammatory actions of insulin would result in enhanced circulating levels of proinflammatory cytokines resulting in persistent low-grade inflammation. A generally enhanced adipose tissue derived cytokine expression may be another plausible mechanism for the inflammation/metabolic syndrome relationship. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, is gaining appreciation. Although the precise role of adipokines in the metabolic syndrome is still debated, an imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may be an intriguing working hypothesis. The proinflammatory state that accompanies the metabolic syndrome associates with both insulin resistance and endothelial dysfunction, providing a connection between inflammation and metabolic processes which is highly deleterious for vascular functions.     

Is central obesity a good predictor of carotid atherosclerosis in Japanese type 2 diabetes with metabolic syndrome?

Metabolic syndrome has been revealed to be a major risk factor for cardiovascular disease (CVD) and early mortality in non-diabetic and diabetic patients. In 2005, the International Diabetes Federation (IDF) and the Examination Committee of Criteria for Diagnosis of Metabolic Syndrome in Japan published new definitions of metabolic syndrome in which central obesity was an indispensable factor. However, the significance of this new definition to CVD in type 2 diabetes has not yet been clarified. A cross-sectional study was conducted with 294 Japanese type 2 diabetic patients without known cardiovascular disease to evaluate the association between metabolic syndrome defined by this new definition and carotid atherosclerosis, and the significance of central obesity for the prediction of the development of carotid atherosclerosis. In a multivariate regression analysis, metabolic syndrome but not central obesity was significantly associated with carotid intima-media thickness (IMT) independent of known cardiovascular risk factors (p<0.05). In addition, whereas carotid IMT was significantly increased according to the increase in the number of components of metabolic syndrome, it was not significantly different between the groups with the same number of components of metabolic syndrome with or without central obesity. These findings suggest that the prediction of the development of carotid atherosclerosis in Japanese type 2 diabetic patients could be improved by the assessment of aggregation of components of metabolic syndrome rather than with or without metabolic syndrome by this new definition.