心外膜脂肪对冠心病的影响及干预进展

心外膜脂肪组织（EAT）是围绕在心脏和冠状动脉周围的特殊内脏脂肪组织。近年来研究发现,EAT是内源性脂肪和促炎因子的重要来源,可调节冠状动脉粥样硬化性心脏病的发生和发展过程。本文回顾了EAT与冠状动脉粥样硬化性心脏病相关的最新研究进展,并对以EAT为干预靶点,发挥治疗冠心病潜能的相关研究进行综述。     

Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.     

肥胖对动脉粥样硬化的影响

肥胖是一种由多种因素引起的慢性代谢性疾病,表现为体内脂肪堆积过多和(或)脂肪分布异常。动脉粥样硬化的主要病变特征是动脉内膜下脂质沉积,伴有平滑肌细胞和胶原纤维增多,逐步发展形成动脉粥样硬化性斑块。大量的基础和临床研究表明,肥胖能够加剧动脉粥样硬化的发生危险,其可能的机制包括脂代谢异常、胰岛素抵抗、炎症、内皮功能障碍等,但是迄今为止肥胖对动脉粥样硬化的影响机制尚未完全清楚。本文将重点从心外膜及血管周围的异位脂肪沉积、新型脂肪因子、脂肪组织相关外泌体、脂肪棕色化等新的观点阐述肥胖对动脉粥样硬化的影响,为肥胖致动脉粥样硬化的防治提供一些新的思路。     

Relationship between C-reactive protein and visceral adipose tissue in healthy Japanese subjects

AIM: Recent studies have suggested that the elevated C-reactive protein (CRP) levels are associated with body fat, especially visceral adipose tissue, but most of them were investigated in Westerners who had higher body mass index (BMI) than Asians. To investigate the association between CRP concentrations, parameters of visceral obesity, the insulin resistance syndrome and carotid atherosclerosis in healthy Japanese who had a lower BMI than Westerners. METHODS: We explored the relationships between fatness and visceral obesity parameters [by anthropometry, bioelectrical impedance analysis and abdominal computed tomography (CT)] and CRP (high sensitivity) and examined their associations with components of insulin resistance syndrome, interleukin-6 (IL-6), tissue necrosis factor-alpha (TNF-alpha) and intima-media thickness (IMT) of common carotid arteries (CCAs) by ultrasonograms in 116 healthy Japanese subjects. RESULTS: In crude regression analyses, CRP was significantly associated with measures of obesity. After adjustment for age, gender and smoking, the association with CRP was stronger for parameters of visceral obesity (waist circumference, waist-to-hip ratio and visceral adipose tissue accumulation) than for other parameters of obesity. IL-6 and TNF-alpha were not associated with CRP. Blood pressure (BP), metabolic variables and CCA-IMT were also significantly associated with CRP. But, after being adjusted for age, gender, smoking and BMI, BP and high-density lipoprotein cholesterol (HDLc) were significantly associated. CONCLUSION: CRP level is associated with visceral adipose tissue and is significantly associated with the components of insulin resistance syndrome in healthy Japanese subjects. These data support a possible role of visceral adipose tissue in inflammation component of atherosclerosis, and further studies are needed to study the mechanism of CRP elevation caused by visceral adipose tissue.     

WILLENDORF AWARDAW0001Establishment of the concept of visceral fat syndrome and the discovery of adiponectin

Clinical studies in recent years have demonstrated that the extent of obesity does not necessarily determine the development of obesity‐related diseases such as type2 diabetes, hyperlipidemia, hypertension, but fat distribution is a much more important determinant In 1983, we reported a method for fat analysis using CT scan which enabled us to analyze in intraabdominal adipose tissue, namely visceral fat as well as subcutaneous fat. Then we demonstrated that visceral fat accumulation correlated to the disturbance of lipid and glucose metabolism, insulin resistance, hypertension and cardiovascular disease in obese subjects and even in non‐obese subjects. From these clinical studies, we proposed the concept of ‘visceral fat syndrome’ in which multiple risk factors cluster through visceral fat accumulation. Besides, this syndrome is designated to be a very atherogenic state. Visceral fat syndrome is corresponding to the concept of metabolic syndrome recently noted. In order to clarify the molecular mechanism why visceral fat accumulation correlates to plural common diseases and also directly to atherosclerosis, we started a project for the analysis of adipose tissue using random sequence of expressed genes in adipose tissues. We found unexpectedly that adipose tissue, especially visceral fat, expressed strongly the genes encoding secretory proteins most of which are important bioactive substances (named as adipocytokines). In addition to known adipocytokines, several novel adipose‐specific genes were identified. Among them, a collagen‐like protein encoded by an adipose most abundant gene (apM‐1) is the most important novel adipocytokine which is named adiponectin. Adiponectin has anti‐diabetic, anti‐atherogenic, anti‐oncogenic and anti‐inflammatory properties and its plasma levels decreases with visceral fat accumulation, suggesting that this molecules may play a central role in the visceral fat syndrome or metabolic syndrome. In this lecture, I would like to present the importance of adiponectin together with other adipocytokines in lifestyle‐related diseases relevant to visceral fat accumulation.     

Human epicardial adipose tissue: a review

We discuss the anatomy, physiology, and pathophysiology of epicardial adipose tissue and its relationship to coronary atherosclerosis. Epicardial fat stores triglyceride to supply free fatty acids for myocardial energy production and produces adipokines. It shares a common embryological origin with mesenteric and omental fat. Like visceral abdominal fat, epicardial fat thickness, measured by echocardiography, is increased in obesity. Epicardial fat could influence coronary atherogenesis and myocardial function because there is no fibrous fascial layer to impede diffusion of free fatty acids and adipokines between it and the underlying vessel wall as well as the myocardium. Segments of coronary arteries lacking epicardial fat or separated from it by a bridge of myocardial tissue are protected against the development of atherosclerosis in those segments. However, when epicardial fat is totally absent in congenital generalized lipodystrophy, coronary atherosclerosis can still occur. Macrophages are more numerous and densely packed in the periadventitial fat of human atherosclerotic coronary arteries with lipid cores than in that of fibrocalcific or nonatherosclerotic coronary arteries. In obese patients with multiple cardiovascular risk factors, epicardial fat around atheromatous coronaries secretes several proinflammatory cytokines and is infiltrated by macrophages, lymphocytes, and basophils. Epicardial adipokine expression in obesity without coronary atherosclerosis has not been determined. In nonobese patients, epicardial fat around atheromatous coronary arteries expresses proinflammatory cytokines but produces either less adiponectin, a vasoprotective adipokine, than fat around nonatheromatous coronaries or a similar amount compared with thoracic subcutaneous fat. Further studies should be done to test the hypothesis that adipokines produced by and released from human epicardial adipose tissue might contribute locally to the pathogenesis of coronary atherosclerosis.     

Adiponectin and hypertension

Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function.     

肥胖患者皮下及内脏脂肪组织中11β-羟基类固醇脱氢酶1的表达

目的检测肥胖患者皮下及内脏脂肪组织中11β-羟基类固醇脱氢酶1（11β—HSD1）含量,了解11β—HSD1在脂肪组织的分布以及与肥胖症之间的关系。方法选取急性阑尾炎手术患者23例,根据BMI分为肥胖组及正常体重组。术中采集肥胖及正常体重者皮下和内脏脂肪组织,运用RT—PCR法及免疫印迹法检测皮下和内脏脂肪组织中11β—HSD1的表达。结果RT-PCR和免疫印迹检测结果显示11β—HSD1在肥胖组及正常体重组皮下及内脏脂肪组织均有表达,其中两组内脏脂肪组织的表达均显著高于皮下脂肪组织表达。组间比较显示,肥胖组内脏脂肪组织中检测到11β-HSD1表达量要显著高于正常体重组,但在两组间皮下脂肪组织中的表达量无明显差异。结论人皮下及内脏脂肪组织均有11β—HSD1的表达,脂肪组织中11β-HSD1的表达与肥胖有关,其主要促进内脏脂肪组织的堆积。     

Gender difference in postprandial lipemia : importance of visceral adipose tissue accumulation.

Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and low HDL-cholesterol concentrations are common features of a plurimetabolic syndrome, which increases the risk of coronary artery disease. Although it has been proposed that the development of atherosclerosis through alterations in plasma lipid levels could be a postprandial phenomenon, most studies on gender differences in plasma lipoprotein-lipid concentrations have reported fasting levels. Therefore, the aim of our study was to examine the response of postprandial triglyceride-rich lipoproteins to a standardized meal in 63 men and 25 women. In addition to the measurement of fasting and postprandial plasma lipid levels, numerous physical and metabolic variables were assessed, including body composition by underwater weighing and body fat distribution by computed tomography. Although no gender difference was noted in total body fat mass, men were characterized by a preferential accumulation of abdominal adipose tissue as revealed by an increased waist circumference and a greater visceral adipose tissue accumulation (50% difference) compared with women (P<0.001). Men also showed a greater plasma triglyceride response (P<0.005) as well as increased postprandial insulin and free fatty acid levels compared with women (P<0.01). Visceral adipose tissue was significantly associated with the postprandial triglyceride response in both genders (men: r=0.49, P<0. 0001; women: r=0.43, P<0.05). Finally, when men and women were matched for visceral adipose tissue accumulation, the gender difference in postprandial plasma triglyceride response was eliminated. Thus results of the present study suggest that the well known gender difference in visceral adipose tissue accumulation is an important contributing factor involved in the exaggerated postprandial triglyceride-rich lipoprotein response noted in men compared with women.     

Relation of body fat distribution in men and degree of coronary narrowings in coronary artery disease.

This study evaluates the relation between body fat distribution and severity of coronary artery disease (CAD). The study sample comprised 33 patients with angiographically demonstrated CAD and 10 angiographically normal control subjects. Body fat distribution was estimated by computed tomography and degree of coronary narrowings by angiographic score. Body weight, body mass index and total and subcutaneous abdominal adipose tissue areas showed no statistical differences in the 2 groups; visceral abdominal adipose tissue area and the visceral to subcutaneous abdominal adipose tissue area ratio were significantly higher in patients with CAD (p < 0.05). There was a significant correlation between visceral fat and triglycerides, apoprotein B and sum of glucose and insulin during glucose oral tolerance test. Sum of insulin during glucose oral tolerance test, visceral abdominal adipose tissue area and visceral/subcutaneous abdominal adipose tissue area ratio correlated significantly with severity of CAD, as evaluated by coronary score in all subjects and in CAD patients alone. Stepwise multiple regression analysis using the coronary score as the dependent variable and anthropometric and metabolic parameters as independent variables shows that in all subjects and in CAD patients alone, visceral/subcutaneous abdominal adipose-tissue area ratio entered the regression first and the sum of insulin during glucose oral tolerance test second. The results suggest that visceral abdominal adipose tissue area and visceral to subcutaneous abdominal adipose tissue area ratio may be cardiovascular risk factors.     

Adipose tissue and atherosclerosis: exploring the connection

The prevalence of obesity, especially among the young, is dramatically increasing in the United States. Obesity is associated with accelerated atherosclerosis and increased rates of cardiovascular death. There are many plausible mechanisms by which an increase in adipose tissue could adversely affect the vessel wall. These include the changes in blood pressure, glucose level, lipid/lipoprotein metabolism, and systemic inflammation. In addition, factors secreted by adipose tissue may directly influence vessel wall homeostasis by influencing the function of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall. There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardio-metabolic risk. Although the basis of this differential risk has not been not established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Numerous studies have shown the beneficial effects of weight loss on markers of cardiovascular risk but fewer have demonstrated improvement in direct measures of large vessel disease. The unfolding role of adipose tissue as an important metabolic and secretory organ provides new opportunities for developing more effective approaches for preventing obesity and its atherosclerotic complications.     

内脏脂肪组织与心肌纤维化研究进展

肥胖与心肌纤维化关系密切,尤其是内脏脂肪组织与心肌纤维化的相关性,引起了医学界的重视。既往有众多研究证实内脏脂肪组织通过分泌瘦素、脂联素等多种脂肪细胞因子参与心肌纤维化,其作用机制较为复杂。而最近研究表明内脏脂肪组织还能通过产生骨桥蛋白促进心肌纤维化。新兴起的测定内脏脂肪组织的生物电阻抗分析法亦将为其进一步的临床应用及研究奠定基础。文章就内脏脂肪组织参与心肌纤维化机制及其测定方法作一综述。     

Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue

Aims/hypothesis

Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals.

Methods

MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RT-PCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals.

Results

We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c⁺CD206⁺ adipose tissue macrophages than in CD11c^?CD206⁺ cells.

Conclusions/interpretation

The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype.     

Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study

Glucocorticoids play an important role in determining adipose tissue metabolism and distribution. Patients with Cushing's syndrome or receiving corticosteroid therapy develop a reversible visceral obesity. In obese patients, although circulating concentrations of cortisol are not consistently elevated, local conversion of inactive cortisone to active cortisol in adipose tissue, catalyzed by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), could amplify glucocorticoid signaling. We have studied, using semiquantitative in situ hybridization, 11beta-HSD-1 mRNA expression in the adipocyte and stromal compartments of sc abdominal adipose tissue obtained from 12 lean patients and sc abdominal and visceral adipose tissue obtained from 18 obese patients. 11beta-HSD-1 mRNA was expressed in adipocytes, stroma, and walls of vessels. Localization of 11beta-HSD-1 mRNA did not differ between lean sc and obese sc or visceral adipose tissue. 11beta-HSD-1 mRNA levels were significantly (P = 0.0106) increased in the adipocyte compartment of sc adipose tissue obtained from obese patients as compared with nonobese ones, whereas no significant change (P = 0.446) was found in the stromal compartment. In obese patients, 11beta-HSD-1 mRNA expression was increased (P = 0.0157) in the stromal compartment of visceral compared with sc tissue, whereas no significant change (P = 0.8767) was found in the adipocyte compartment. In summary, our data show that 11beta-HSD-1 mRNA is increased in adipose tissue from obese patients, in the abdominal sc fat in adipocytes and in the visceral fat in both adipocytes and stroma. This observation suggests that an overexpression of 11beta-HSD-1 may explain part of the glucocorticoid-induced metabolic disorders linked to obesity and may promote visceral fat deposition.     

Adiposopathy: Treating pathogenic adipose tissue to reduce cardiovascular disease risk

Opinion statement Excessive adipose tissue is potentially pathogenic due to its mass effects and through adverse metabolic/immune responses, which may lead to cardiovascular disease risk factors (eg, type 2 diabetes mellitus, hypertension, dyslipidemia, and possibly atherosclerosis itself). Positive caloric balance in genetically/environmentally susceptible patients may result in adipocyte hypertrophy, visceral adipose tissue accumulation, and ectopic fat deposition, all causally associated with metabolic disease, and all anatomic manifestations of “adiposopathy” (a term used to describe adipose tissue pathology). Weight loss through improved nutrition, increased physical activity, and weight loss agents (ie, orlistat and sibutramine) improves adiposopathy and improves many metabolic diseases whose prevalence are directly associated with an increase in body fat and sedentary lifestyle. Cannabinoid receptor antagonists improve adiposopathy through weight reduction and favorable metabolic effects upon multiple body organs (including adipocytes). Peroxisome proliferator-activated receptor-γ agonists may improve adiposopathy through recruitment of functional fat cells and apoptosis of dysfunctional fat cells.     

Increased visceral adipose tissue rather than BMI as a risk factor for dementia

In addition to the association between overweight/obesity and cardiovascular disorders, with the presence of a vascular burden as a cofactor, recent studies have particularly focused on the association between indicators of adiposity and dementia. Particularly, renewed predictive value has been addressed to body mass index (BMI). A high BMI can increase the risk for dementia when measured before clinical dementia onset. Although the use of BMI in population-based and clinical studies is feasible, this is an index of weight excess and shows limits in its ability to distinguish between fat and fat-free mass or between deep (visceral) abdominal fat and subcutaneous abdominal fat. In this scenario, we suggest that visceral adipose tissue (VAT) rather than BMI should be considered as a concurrent factor in the development of dementia. Several physiopathologic theories (neurochemical, hormonal, atherosclerotic and inflammatory) have been proposed to explain the decline of cognitive functions. Along with this, well known cardiovascular risk factors (dyslipidaemia, insulin resistance, blood pressure, adipocytokine/chemokines, atherosclerosis) contributing to the development of cognitive decline seem more strongly related to body fat distribution, particularly visceral adipose tissue (VAT), rather than to BMI. With this regard, VAT may be reasonably considered to play a predominant role.     

Adipose Tissue: A Metabolic Regulator. Potential Implications for the Metabolic Outcome of Subjects Born Small for Gestational Age (SGA)

Adipose tissue is involved in the regulation of glucose and lipid metabolism, energy balance, inflammation and immune response. Abdominal obesity plays a key role in the development of insulin resistance because of the high lipolytic rate of visceral adipose tissue and its secretion of adipocytokines. Low birth weight subjects are prone to central redistribution of adipose tissue and are at high risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Intrauterine adipogenesis may play a key role in the fetal origin of the pathogenesis of metabolic syndrome, type 2 diabetes and cardiovascular disease. Therefore, knowledge of the behavior of visceral adipose tissue-derived stem cells could provide a greater understanding of the metabolic risk related to intrauterine growth retardation, with potential clinical implications for the prevention of long-term metabolic alterations.     

ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

Perivascular adipose tissue surrounds (coronary) arteries and may be involved in local stimulation of atherosclerotic plaque formation. Epicardial adipose tissue, the adipose tissue within the pericardium, is a frequently used measure of coronary perivascular adipose tissue and can be quantified with echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI). The quantity of (coronary) perivascular adipose tissue is correlated with parameters of the metabolic syndrome, such as increased waist circumference, hypertriglyceridemia and hyperglycemia, and with coronary atherosclerosis. Coronary artery segments covered by myocardium are not exposed to coronary perivascular adipose tissue and interestingly, atherosclerosis is absent in these intra-myocardial segments. Pro-inflammatory cytokines and adipokines are expressed and secreted at a higher level in epicardial adipose tissue of patients with coronary artery disease compared to patients without coronary artery disease. Furthermore, in vitro and ex vivo perivascular adipose tissue induces inflammation of the artery wall by secretion of pro-inflammatory proteins. Atherogenesis in the vascular wall is thus stimulated from ‘outside to inside’. Based on the results of clinical, ex vivo and in vitro studies, it can be argued that perivascular adipose tissue may be involved in the process of atherosclerosis.     

Visceral, subcutaneous or intramuscular fat: where is the problem?

The adipose tissue is a dynamic organ that secrets several factors, denominated adipokines. They are associated, directly or indirectly, in a process that contributes to atherosclerosis, hypertension, insulinic resistance and diabetes type 2, dyslipidemias, presenting the link between adiposity, metabolic syndrome and cardiovascular diseases. In the obesity, body fat depots are increased, presenting eventual elevation in the adipokines expression and secretion. The different fat depots, visceral, abdominal subcutaneous, gluteal-femoral subcutaneous and intramuscular adipose tissue, have different metabolic and endocrine degrees, interfering, therefore, with specific form in the process associated with body adiposity in obese and diabetics subjects. The present study seeks to discuss the endocrine and metabolic role of each adipose tissue compartment, by way to assess their contribution to the complications linked to obesity.