脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

The Roles of Adipokines,Proinflammatory Cytokines,and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.     

The renin–angiotensin system in adipose tissue and its metabolic consequences during obesity

Obesity is a worldwide disease that is accompanied by several metabolic abnormalities such as hypertension, hyperglycemia and dyslipidemia. The accelerated adipose tissue growth and fat cell hypertrophy during the onset of obesity precedes adipocyte dysfunction. One of the features of adipocyte dysfunction is dysregulated adipokine secretion, which leads to an imbalance of pro-inflammatory, pro-atherogenic versus anti-inflammatory, insulin-sensitizing adipokines. The production of renin–angiotensin system (RAS) components by adipocytes is exacerbated during obesity, contributing to the systemic RAS and its consequences. Increased adipose tissue RAS has been described in various models of diet-induced obesity (DIO) including fructose and high-fat feeding. Up-regulation of the adipose RAS by DIO promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling, all of which worsen the adipose environment. Consequently, the increase of circulating RAS, for which adipose tissue is partially responsible, represents a link between hypertension, insulin resistance in diabetes and inflammation during obesity. However, other nutrients and food components such as soy protein attenuate adipose RAS, decrease adiposity, and improve adipocyte functionality. Here, we review the molecular mechanisms by which adipose RAS modulates systemic RAS and how it is enhanced in obesity, which will explain the simultaneous development of metabolic syndrome alterations. Finally, dietary interventions that prevent obesity and adipocyte dysfunction will maintain normal RAS concentrations and effects, thus preventing metabolic diseases that are associated with RAS enhancement.     

Adipokines: molecular links between obesity and atheroslcerosis

Atherosclerotic disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment, and prevention. The increasing epidemic of obesity, insulin resistance, and diabetes will likely add to this burden. Increasingly, it is becoming apparent that adipose tissue is an active endocrine and paracrine organ that releases several bioactive mediators that influence not only body weight homeostasis but also inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, and atherosclerosis. The cellular mechanisms linking obesity and atherosclerosis are complex and have not been fully elucidated. This review summarizes the experimental and clinical evidence on how excess body fat influences cardiovascular health through multiple yet converging pathways. The role of adipose tissue in the development of obesity-linked insulin resistance, metabolic syndrome, and diabetes will be reviewed, including an examination of the molecular links between obesity and atherosclerosis, namely, the effects of fat-derived adipokines. Finally, we will discuss how these new insights may provide us with innovative therapeutic strategies to improve cardiovascular health.     

Adipose tissue: between the extremes

Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole‐body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity‐related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies.     

Oxidative stress and lipid peroxidation by-products at the crossroad between adipose organ dysregulation and obesity-linked insulin resistance

Obesity has been proposed as an energy balance disorder in which the expansion of adipose tissue (AT) leads to unfavorable health outcomes. Even though adiposity represents the most powerful driving force for the development of insulin resistance (IR) and type 2 diabetes, mounting evidence points to “adipose dysregulation”, rather than fat mass accrual per se, as a key pathophysiological trigger of the obesity-linked metabolic complications. The dysfunctional fat, besides hypertrophic adipose cells and inflammatory cues, displays a reduced ability to form new adipocytes from the undifferentiated precursor cells (ie, the preadipocytes). The failure of adipogenesis poses a “diabetogenic” milieu either by promoting the ectopic overflow/deposition of lipids in non-adipose targets (lipotoxicity) or by inducing a dysregulated secretion of different adipose-derived hormones (ie, adipokines and lipokines). This novel and provocative paradigm (“expandability hypothesis”) further extends current “adipocentric view” implicating a reduced adipogenic capacity as a missing link between “unhealthy” fat expansion and impairment of metabolic homeostasis.     

Sex differences in human adipose tissues – the biology of pear shape

Women have more body fat than men, but in contrast to the deleterious metabolic consequences of the central obesity typical of men, the pear-shaped body fat distribution of many women is associated with lower cardiometabolic risk. To understand the mechanisms regulating adiposity and adipose tissue distribution in men and women, significant research attention has focused on comparing adipocyte morphological and metabolic properties, as well as the capacity of preadipocytes derived from different depots for proliferation and differentiation. Available evidence points to possible intrinsic, cell autonomous differences in preadipocytes and adipocytes, as well as modulatory roles for sex steroids, the microenvironment within each adipose tissue, and developmental factors. Gluteal-femoral adipose tissues of women may simply provide a safe lipid reservoir for excess energy, or they may directly regulate systemic metabolism via release of metabolic products or adipokines. We provide a brief overview of the relationship of fat distribution to metabolic health in men and women, and then focus on mechanisms underlying sex differences in adipose tissue biology.     

Vaspin gene in rat adipose tissue: relation to obesity-induced insulin resistance

Visceral adipose fat has been claimed to be the link between obesity and insulin resistance through the released adipokines. This study aimed to assess the expression of vaspin as one of the recent adipokines in rats abdominal subcutaneous and visceral fat in diet-induced obese (DIO) and in DIO performing 3 weeks swimming exercise (DIO + EXE) compared to control and control + exercise (C + EXE) groups. Vaspin mRNA and protein expression assessed using RT-PCR and Western blotting analysis revealed vaspin expression in DIO and DIO + EXE but not in controls groups. In DIO group, visceral vaspin expression was higher than in that of subcutaneous fat and was positively correlated with body weight. Upregulation of visceral vaspin expression in DIO was concomitant with the development of insulin resistance (increase in fasting serum insulin and HOMA-IR) and rise in serum leptin level. Unchanged visceral vaspin mRNA in DIO + EXE rats, with significant improvements of insulin resistance parameters and serum leptin compared to DIO group was found. In conclusion, increased visceral vaspin expression in obesity was associated with insulin resistance. Further investigations into the molecular links between vaspin and obesity may unravel innovative therapeutic strategies in people affected by obesity-linked insulin resistance, metabolic syndrome, and type 2 diabetes.     

Sex differences in human adipose tissues - the biology of pear shape

ABSTRACT: Women have more body fat than men, but in contrast to the deleterious metabolic consequences of the central obesity typical of men, the pear-shaped body fat distribution of many women is associated with lower cardiometabolic risk. To understand the mechanisms regulating adiposity and adipose tissue distribution in men and women, significant research attention has focused on comparing adipocyte morphological and metabolic properties, as well as the capacity of preadipocytes derived from different depots for proliferation and differentiation. Available evidence points to possible intrinsic, cell autonomous differences in preadipocytes and adipocytes, as well as modulatory roles for sex steroids, the microenvironment within each adipose tissue, and developmental factors. Gluteal-femoral adipose tissues of women may simply provide a safe lipid reservoir for excess energy, or they may directly regulate systemic metabolism via release of metabolic products or adipokines. We provide a brief overview of the relationship of fat distribution to metabolic health in men and women, and then focus on mechanisms underlying sex differences in adipose tissue biology.     

Appetite and energy balance signals from adipocytes

Interest in the biology of white adipose tissue has risen markedly with the recent surge in obesity and its associated disorders. The tissue is no longer viewed simply as a vehicle for lipid storage; instead, it is recognized as a major endocrine and secretory organ. White adipocytes release a multiplicity of protein hormones, signals and factors, termed adipokines, with an extensive range of physiological actions. Foremost among these various adipokines is the cytokine-like hormone, leptin, which is synthesized predominantly in white fat. Leptin plays a critical role in the control of appetite and energy balance, with mutations in the genes encoding the hormone or its receptor leading to profound obesity in both rodents and man. Leptin regulates appetite primarily through an interaction with hypothalamic neuroendocrine pathways, inhibiting orexigenic peptides such as neuropeptide Y and orexin A, and stimulating anorexigenic peptides such as proopiomelanocortin. White fat also secretes several putative appetite-related adipokines, which include interleukin-6 and adiponectin, but whether these are indeed significant signals in the regulation of food intake has not been established. Through leptin and the other adipokines it is evident that adipose tissue communicates extensively with other organs and plays a pervasive role in metabolic homeostasis.     

Lipokines and oxysterols: Novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance

The expansion of adipose tissue (AT) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a “healthy” fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, “unhealthy” AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the “AT expandability” paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipokines and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/β-catenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions.     

Adipokines oversecreted by omental adipose tissue in human obesity

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.     

The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease

Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction.     

The double role of epicardial adipose tissue as pro- and anti-inflammatory organ.

Obesity is associated with low grade inflammation. Whether this is just an adaptive response to excess adiposity to maintain a normal oxygen supply or a chronic activation of the innate immune system is still unknown. Recent research has focused on the origin of the inflammatory markers in obesity and the extent to which adipose tissue has a direct effect. The production of adipokines by visceral adipose tissue is of particular interest since their local secretion by visceral fat depots may provide a novel mechanistic link between obesity and the associated vascular complications. Growing evidences suggest that the epicardial adipose tissue, the visceral fat depot located around the heart, may locally interact with myocardium and coronary arteries. Epicardial fat is a source of adiponectin and adrenomedullin, adipokines with anti-inflammatory properties, and several proinflammatory cytokines as well as Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin 1 (IL1), IL-1 h, Interleukin (IL6), Monocyte Chemoattractive Protein-1 (MCP-1), Nerve Growth Factor (NGF), resistin, Plasminogen Activator Inhibitor-1 (PAI-1), and free fatty acids. Epicardial adipose tissue could locally modulate the heart and vasculature, through paracrine secretion of pro- and anti-inflammatory cytokines, thereby playing a possible role in the adiposity-related inflammation and atherosclerosis. On the other hand, epicardial fat could exert a protective effect through adiponectin and adrenomedullin secretion as response to local or systemic metabolic or mechanical insults. Future studies will continue to provide new and fascinating insights into the double role of epicardial adipose tissue in the development of cardiovascular pathology and/or in protecting the heart and arteries.     

脂肪细胞因子对代谢的调节

脂肪组织可将多余能量以甘油三酯(triglycerides,TG)形式储存,在饥饿状态下可分解TG产生游离脂肪酸(free fatty acids,FFAs)为机体供能。此外,脂肪组织还具有体温调节和器官保护功能,并且越来越多的证据表明,脂肪组织也是一种重要的内分泌组织。脂肪组织分泌的蛋白质物质被称为脂肪细胞因子(adipokine),可通过自分泌、旁分泌和内分泌方式发挥多种生物学功能,例如调节能量摄入和能量消耗,调节糖脂代谢,抗炎和促炎反应。对整体而言,脂肪细胞因子可调节大脑、肝、肌肉、血管系统、心、胰腺和免疫系统等不同靶器官的生物反应。其中,脂肪细胞因子在糖脂代谢中发挥特定的作用,包括:葡萄糖代谢[瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)];胰岛素敏感性 [瘦素、脂联素、锌-α2-糖蛋白(zinc-α2-glycoprotein,ZAG)];脂肪形成[骨形成蛋白4(bone morphogenetic protein 4,BMP4)]等生物反应过程。但目前对脂肪组织功能障碍与代谢之间机制的理解尚不完善。脂肪组织功能发生紊乱时,脂肪细胞因子的分泌会发生改变,并可能导致一系列与肥胖相关的代谢性疾病的发生。临床前和临床研究表明,激活或抑制特定脂肪细胞因子的信号转导可能是一种适合干预代谢疾病的方法。本文就部分脂肪细胞因子对代谢的调控作用做出综述,以增强对脂肪细胞因子功能的理解。     

Hypothalamic inflammation and thermogenesis: the brown adipose tissue connection

Hypothalamic inflammation and dysfunction are common features of experimental obesity. An imbalance between caloric intake and energy expenditure is generated as a consequence of this inflammation, leading to the progressive increase of body adiposity. Thermogenesis, is one of the main functions affected by obesity-linked hypothalamic dysfunction and the complete characterization of the mechanisms involved in this process may offer new therapeutic perspectives for obesity. The brown adipose tissue is an important target for hypothalamic action in thermogenesis. This tissue has been thoroughly studied in rodents and hibernating mammals; however, until recently, its advocated role in human thermogenesis was neglected due to the lack of substantial evidence of its presence in adult humans. The recent demonstration of the presence of functional brown adipose tissue in adult humans has renovated the interest in this tissue. Here, we review some of the work that shows how inflammation and dysfunction of the hypothalamus can control brown adipose tissue activity and how this can impact on whole body thermogenesis and energy expenditure.     

Pharmacological and non-pharmacological interventions to influence adipose tissue function

Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-γ agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes.     

Apoptosis Through Targeted Activation of Caspase8 (“ATTAC-mice”): Novel Mouse Models of Inducible and Reversible Tissue Ablation

Recent studies identifying obesity as a significant and increasingly more common cause of morbidity and mortality have intensified research efforts aimed at increasing our understanding of adipose tissue biology. These efforts have culminated in the discovery of several adipokines, or adipose tissue-derived hormones, that have been implicated in the regulation of multiple physiological functions, as well as the realization that adipose tissue dysfunction plays an important role in the pathogenesis of diseases such as obesity and diabetes. To better understand the role of adipose tissue in these physiological/pathological events, several studies have employed transgenic strategies to eliminate adipose tissue. However, these mouse models of congenital lipoatrophy/lipodystrophy exhibit severe metabolic and somatic cell dysfunction. To circumvent this limitation, we have characterized the first inducible fatless mouse. The FAT-ATTAC mouse is a transgenic model whereby expression of a myristoylated caspase 8-FKBP fusion protein enables selective ablation of adipocytes via induction of apoptosis that occurs upon treatment with a chemical dimerizer. The FAT-ATTAC mouse model not only has the advantage that adipocyte ablation be induced at any time during development, but it is also fully reversible, as adipose tissue regenerates after cessation of dimerizer treatment. The inducibility of this fatless mouse model holds potential for revealing novel physiological roles for adipose tissue as well as its contribution to the etiology and pathogenesis of various disease states. Here we describe several ongoing areas of research employing the FAT-ATTAC mouse; in addition we describe potential uses of the targeted transgenic apoptotic approach to study other cell types of interest.