Update on therapeutic strategies to increase adiponectin function and secretion in metabolic syndrome

Changes in diagnostic criteria have impacted on the definition of the metabolic syndrome. The central aetiological importance of insulin resistance has lessened, while the role of other cardiovascular risk factors has progressively increased. Inflammatory mediators have also been identified as crucial targets for more selective therapies in metabolic syndrome. Among several pro-inflammatory factors, adiponectin has been shown to be associated with reduced cardiovascular risk in metabolic syndrome patients. Here, we review new therapeutic approaches, which could potentially increase adiponectin levels in metabolic syndrome.     

脂氧素与代谢性疾病的研究进展

脂氧素(LX)是体内重要的内源性脂质抗炎介质,来源于花生四烯酸,具有抗炎和促炎症消退的作用。近年来, LX在糖尿病、肥胖、心血管疾病等代谢性疾病中的作用引起广泛关注。为此,本文就LX的生物学作用,以及其在代谢性疾病中的研究进展做一简要综述。     

炎症Caspase调控固有免疫在心血管疾病中的作用

越来越多的证据表明,慢性炎症与高血压、动脉粥样硬化等心血管疾病密切相关。半胱天冬氨酸蛋白水解酶(Caspase)亚型Caspase-1、4、5和11被称为炎症Caspase,通过促进炎症因子的成熟与释放,诱导放大炎症反应,激活固有免疫应答。炎症Caspase作用机制包括两方面,一方面激活模式识别受体NLRP3炎症小体,促进炎症因子白细胞介素1β(IL-1β)和IL-18的剪切成熟,另一方面剪切Gasdermin D形成具有膜上打孔作用的N端,导致细胞焦亡,促进炎症因子释放。文章就炎症Caspase在心血管疾病中的作用进行综述。     

The metabolic syndrome in critically ill patients

Metabolic support in intensive care is a rapidly evolving field with new information being gathered almost on a daily basis. In endocrine practice, over the last 20 years, researchers have focussed on a new entity, termed the "metabolic syndrome". This describes the constellation of abnormalities which include central adiposity, insulin resistance and inflammation. All of these predispose the individual to a greater risk of cardiovascular events. Of interest is the observation that some of the metabolic abnormalities in sepsis and multiple organ dysfunction syndrome of critical illness share several common features with that of the metabolic syndrome. In this chapter we describe the features of the metabolic syndrome as is understood in endocrine parlance, the metabolic abnormalities of critical illness and explore the common threads underlying the pathophysiology and the treatment of the two syndromes. The role of adiponectin in the metabolic abnormalities in both the metabolic syndrome and in sepsis are reviewed. The potential role of the pleiotropic effects of statins in the therapy of sepsis is also discussed.     

Serum adiponectin level is not only decreased in metabolic syndrome but also in borderline metabolic abnormalities

Objective:

Along with the increasing prevalence of obesity and related diseases, particularly atherosclerotic diseases, metabolic syndrome (MetS) is now a common and major public health issue in many countries around the world. Adiponectin, a protein secreted by the adipose tissue, has become recognized as a key player in the development of MetS. These days, not only MetS but also borderline metabolic/physiological abnormalities, such as impaired fasting glucose, high normal blood pressure and high normal plasma cholesterol, have been reported to be risk factors for atherosclerotic disease. Therefore, we undertook this study to determine the relationship between adiponectin and borderline metabolic/physiological abnormalities, as well as MetS.

Design:

A cross-sectional study performed from April 2007 to November 2009.

Subjects:

In 16 892 Japanese adults (10 008 men and 6884 women), we examined the relationship between the serum adiponectin concentration and borderline metabolic/physiological abnormalities or MetS by a questionnaire survey about medical treatment, body size measurement and measurement of laboratory parameters including the serum adiponectin concentration.

Results:

Adiponectin showed a significant negative correlation with the number of MetS components. In subjects without overt diabetes mellitus, hypertension or dyslipidemia, the adiponectin concentration also showed a significant negative correlation with the number of borderline metabolic abnormalities.

Conclusion:

The decrease of circulating adiponectin may start before the development of diabetes mellitus, hypertension, dyslipidemia or MetS. Adiponectin is an important biomarker for reflecting the adverse influence of visceral fat in persons with MetS, and also in these subclinical states.     

铁死亡在代谢性心血管疾病中的作用

铁死亡是一种程序性细胞死亡方式,其特征是细胞亚铁离子及大量脂质过氧化物的积累。代谢性心血管疾病是由一系列代谢因素参与的以心血管功能损害为特征的疾病。越来越多的研究表明铁死亡在代谢性心血管疾病的发生发展中发挥着重要的作用。探究铁死亡在代谢性心血管疾病中的作用,对揭示代谢性心血管疾病的发病机制和防治策略具有重要的临床意义。     

Advances in the understanding of mast cell function

Mast cells were formerly thought to contribute mainly to, sometimes even, fatal allergic reactions through the release of biologically highly active cytokines, chemokines, lipid mediators, proteases and biogenic amines. This potential harmful response is triggered by crosslinking of cell-bound IgE by the respective allergen. This review updates our current understanding of the emerging roles of mast cells with an emphasis on their relevance in protective host immunity. The activation of mast cells independently of Immunoglobulin E can lead to the initiation of fast inflammatory reactions, which were shown to be life-saving in murine models of bacterial infections. Besides their critical functions in innate immunity, mast cells promote and shape the development of adaptive immune responses. Thus, mast cells are increasingly being recognized as sentinels of innate and modulators of adaptive immunity.     

脂联素水平及基因多态性与代谢综合征的关系

目的:探讨脂联素(APN)水平及其单核苷酸基因多态性(SNP) +45T/G和+276G/T两个位点与代谢综合征(MS)的关系.方法:238例研究对象分为对照组和MS组,采用实验-对照研究方法,应用酶联免疫吸附法(ELISA)及聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,对血浆APN浓度及其2个位点基因多态性进行检测.结果:与对照组比较,MS组APN水平降低(P＜0.05);MS组SNP+276T等位基因分布明显升高,多因素逐步Logistic回归分析显示SNP+276基因多态性为MS危险因素.结论:MS患者APN水平下降,携带SNP+276T等位基因者患MS的风险增加.     

血清脂联素与新诊断2型糖尿病病人及代谢综合征患者的关系

目的对血清脂联素水平与新诊断2型糖尿病及代谢综合征患者的关系进行观察和分析。方法测定140例新诊断2型糖尿病患者与80例非糖尿病患者空腹血清脂联素及血糖、血脂、血压等指标，并分析各指标与脂联素的相关性。结果（1）新诊断2型糖尿病患者的血清脂联素水平显著降低。（2）随着代谢综合征指标的增多，脂联素含量呈下降趋势。（3）新诊断为糖尿病组中脂联素与代谢综合征、男性、体重指数呈负相关，与高密度脂蛋白胆固醇呈正相关。结论血清脂联素浓度与2型糖尿病及代谢综合征密切相关，低脂联素血症是糖尿病及代谢综合征的又一特征，在其发病中可能起重要的作用。     

Unexpected protective role for Toll-like receptor 3 in the arterial wall

The critical role of Toll-like receptors (TLRs) in mammalian host defense has been extensively explored in recent years. The capacity of about 10 TLRs to recognize conserved patterns on many bacterial and viral pathogens is remarkable. With so few receptors, cross-reactivity with self-tissue components often occurs. Previous studies have frequently assigned detrimental roles to TLRs, in particular to TLR2 and TLR4, in immune and cardiovascular disease. Using human and murine systems, we have investigated the consequence of TLR3 signaling in vascular disease. We compared the responses of human atheroma-derived smooth muscle cells (AthSMC) and control aortic smooth muscle cells (AoSMC) to various TLR ligands. AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent functional responses. Intriguingly, exposure to dsRNA in vitro and in vivo induced increased expression of both pro- and anti-inflammatory genes in vascular cells and tissues. Therefore, we sought to assess the contribution of TLR3 signaling in vivo in mechanical and hypercholesterolemia-induced arterial injury. Surprisingly, neointima formation in a perivascular collar-induced injury model was reduced by the systemic administration of the dsRNA analog Poly(I:C) in a TLR3-dependent manner. Furthermore, genetic deletion of TLR3 dramatically enhanced the development of elastic lamina damage after collar-induced injury. Accordingly, deficiency of TLR3 accelerated the onset of atherosclerosis in hypercholesterolemic ApoE(-/-) mice. Collectively, our data describe a protective role for TLR signaling in the vessel wall.     

先天性免疫在钙化性主动脉瓣疾病中的作用

钙化性主动脉瓣疾病(CAVD)是影响心脏瓣膜的最常见疾病,其特征是主动脉瓣瓣小叶的增厚、纤维化和矿化,目前尚无有效的药物治疗。主动脉瓣钙化是一个复杂的、多因素影响的过程,包括瓣膜炎症、纤维化、钙化以及瓣膜增厚和心流出道阻塞。CAVD的确切病理生理机制尚不完全清楚,但许多研究表明先天免疫细胞在主动脉瓣钙化的发展中起关键作用。该综述主要阐述目前关于先天性免疫细胞在CAVD发展中的作用。     

宁夏回族代谢综合征与脂联素水平及基因多态性的相关性研究

目的探讨脂联素水平及其单核苷酸多态性(SNP+45T/G和SNP+276G/T)2个位点与宁夏回族代谢综合征(MS)的关系。方法选择祖居宁夏、无亲缘关系、3代内无异族通婚史的回族个体共305例,分为MS组207例和对照组98例;应用ELISA及PCR-RFLP技术检测血浆脂联素水平及其2个位点的SNP。结果与对照组比较,MS组体重指数、腰臀比、收缩压、舒张压、空腹血糖、空腹胰岛素、TG、LDL-C、胰岛素抵抗指数明显升高,TC、HDL-C、脂联素水平明显降低,差异有统计学意义(P<0.05,P<0.01)。与对照组比较,MS组SNP+45位点TG+GG基因型和G等位基因频率明显升高,TT基因型及T等位基因频率明显降低,差异有统计学意义(P<0.01)。多因素逐步logistic回归分析显示,SNP+45T/G基因多态性是回族MS的危险因素。结论回族MS患者脂联素水平下降,回族人群中携带SNP+45G等位基因者患MS的风险增加。     

Clinical immune characterization of hepatitis B virus infection and implications for immune intervention: Progress and challenges

The host immune response plays an important role in mediating hepatitis B virus (HBV) control and induction of liver damage, which determines the outcome of infection. However, interactions between HBV, the immune system, and the liver microenvironment, remain poorly understood. This review briefly outlines what we know about innate and adaptive immune responses to HBV, as well as the liver immunology in infected patients. It addresses how our knowledge of the anti-HBV immune response might aid the development of adoptive immune therapeutic strategies against HBV. This review also highlights the challenges we are facing in understanding the cellular and molecular mechanisms bywhich the innate, adaptive and liver immune responses exert a synergistic antiviral function and influence disease progression. It concludes by addressing future directions and unanswered questions regarding the use of clinical immunotherapy. We hope this review will help hepatologists and gastroenterologists to understand the anti-HBV immune response, as well as current challenges and potential immunotherapeutic strategies against this disease.     

The application of organoid models in research into metabolic diseases

Metabolic diseases have become a major threat to human health worldwide as a result of changing lifestyles. The exploration of the underlying molecular mechanisms of metabolic diseases and the development of improved therapeutic methods have been hindered by the lack of appropriate human experimental models. Organoids are three-dimensional in vitro models of self-renewing cells that spontaneously self-organize into structures similar to the corresponding in vivo tissues, recapitulating the original tissue function. Off-body organoid technology has been successfully applied to disease modelling, developmental biology, regenerative medicine, and tumour precision medicine. This new generation of biological models has received widespread attention. This article focuses on the construction process and research progress with regard to organoids related to metabolic diseases in recent years, and looks forward to their prospective applications.     

Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome

Abstract. Henneman P, Janssens ACJW, Carola Zillikens M, Frolich M, Frants RR, Oostra BA, van Duijn CM, van Dijk KW (Leiden University Medical Center, Leiden; Erasmus Medical Center, Rotterdam, The Netherlands). Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome. J Intern Med 2010; 267 : 402–409. Objective. Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. Design. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre‐ and postmenopausal women and younger and older men. Results. Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9–44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Conclusions. Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS.     

High adiponectin concentration and its role for longevity in female centenarians

Background:   Evidence from experimental models of longevity indicates that maintenance of energy homeostasis could be indispensable for longevity across various species. In humans, it has been reported that maintenance of glucose homeostasis and vascular stability is one biomedical feature of centenarians, who have reached the maximum life-span. We hypothesized that adiponectin, a novel anti-inflammatory adipocytokine, could be a protective factor against age-related metabolic alteration and atherogeneity in centenarians.
Methods:   We measured plasma adiponectin concentration in 66 female centenarians and body mass index (BMI)-matched female controls (mean age 28.3 ± 6.3 years), followed by a genetic analysis of adiponectin locus.
Results:   As compared to BMI-matched female controls, female centenarians had significantly higher plasma adiponectin concentrations. In addition, high concentrations of plasma adiponectin in centenarians was associated with favorable metabolic indicators, and with lower levels of C-reactive protein and E-selectin. In contrast, genetic analysis of 10 single nucleotide polymorphism (SNP) at adiponectin locus did not show significant association between the adiponectin gene variation and longevity.
Conclusions:   Our results suggested that hyperadiponectinemia in centenarians could play a role in maintenance of energy homeostasis and vascular stability, and may contribute to longevity.     

Adiponectin--a key adipokine in the metabolic syndrome

Adiponectin is a recently described adipokine that has been recognized as a key regulator of insulin sensitivity and tissue inflammation. It is produced by adipose tissue (white and brown) and circulates in the blood at very high concentrations. It has direct actions in liver, skeletal muscle and the vasculature, with prominent roles to improve hepatic insulin sensitivity, increase fuel oxidation [via up-regulation of adenosine monophosphate-activated protein kinase (AMPK) activity] and decrease vascular inflammation. Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in the liver. In contrast to other adipokines, adiponectin secretion and circulating levels are inversely proportional to body fat content. Levels are further reduced in subjects with diabetes and coronary artery disease. Adiponectin antagonizes many effects of tumour necrosis factor-alpha(TNF-alpha) and this, in turn, suppresses adiponectin production. Furthermore, adiponectin secretion from adipocytes is enhanced by thiazolidinediones (which also act to antagonize TNF-alpha effects). Thus, adiponectin may be the common mechanism by which TNF-alpha promotes, and the thiazolidinediones suppress, insulin resistance and inflammation. Two adiponectin receptors, termed AdipoR1 and AdipoR2, have been identified and these are ubiquitously expressed. AdipoR1 is most highly expressed in skeletal muscle and has a prominent action to activate AMPK, and hence promote lipid oxidation. AdipoR2 is most highly expressed in liver, where it enhances insulin sensitivity and reduces steatosis via activation of AMPK and increased peroxisome-proliferator-activated receptor alpha ligand activity. T-cadherin, which is expressed in endothelium and smooth muscle, has been identified as an adiponectin-binding protein with preference for HMW adiponectin multimers. Given the low levels of adiponectin in subjects with the metabolic syndrome, and the beneficial effect of the adipokine in animal studies, there is exciting potential for adiponectin replacement therapy in insulin resistance and related disorders.