Adiponectin and cardiovascular health: an update

The global epidemic of obesity is accompanied by an increased prevalence of cardiovascular disease (CVD), in particular stroke and heart attack. Dysfunctional adipose tissue links obesity to CVD by secreting a multitude of bioactive lipids and pro-inflammatory factors (adipokines) with detrimental effects on the cardiovascular system. Adiponectin is one of the few adipokines that possesses multiple salutary effects on insulin sensitivity and cardiovascular health. Clinical investigations have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for CVD. In animals, elevation of plasma adiponectin by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction and diabetic cardiomyopathy. Furthermore, many therapeutic benefits of the peroxisome-proliferator activated receptor gamma agonists, the thiazolidinediones, are mediated by induction of adiponectin. Adiponectin protects cardiovascular health through its vasodilator, anti-apoptotic, anti-inflammatory and anti-oxidative activities in both cardiac and vascular cells. This review summarizes recent findings in the understanding of the physiological role and clinical relevance of adiponectin in cardiovascular health, and in the identification of the receptor and postreceptor signalling events that mediate the cardiovascular actions of adiponectin. It also discusses adiponectin-targeted drug discovery strategies for treating obesity, diabetes and CVD. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.     

脂联素与代谢综合征

脂联素（APN）在＋276T/G、＋45T/G、164I/T、＋10211T/G、-11391G/A、-11377G/C等位点的基因多态性与代谢综合征（MS）及其相关性疾病有关。APN水平与三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）独立相关,血清APN水平降低是独立于体脂因素的胰岛素敏感性的因素之一,APN与2型糖尿病（T2DM）呈强负相关,APN水平与高血压发病呈独立负相关,低APN水平是MS的一个独立危险因素,血清APN水平降低是MS的特征性标志。APN水平与无粥样斑块的颈动脉内膜中层厚度呈负相关,是动脉粥样硬化早期的独立预测因子。APN与MS密切相关。     

Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine

Genome-wide scanning is a powerful tool to identify susceptible chromosome loci, however, individual chromosomal regions still have many candidate genes. Although cDNA microarray analysis provides valuable information for identifying genes involved in pathogenesis, expression levels of many genes are changed. A novel approach for identification of therapeutic targets is the combination of genome-wide scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we screened for secreted molecules, the expressions of which were changed in adipose tissues from mice rendered insulin resistance. Decreased expression of one of these molecules, adiponectin/Acrp30, correlates strongly with insulin resistance. Interestingly, recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where adiponectin gene is located. Decreasing serum adiponectin levels are associated with increased risk for type 2 diabetes. Interestingly, adiponectin was decreased in insulin resistant rodent models both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated their insulin resistance. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes Adiponectin knockout mice showed insulin resistance and glucose intolerance. In muscle and liver, adiponectin activated AMP kinase and PPARalpha pathways thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated insulin resistance under a high-fat diet. Despite similar plasma glucose and lipid levels on an apoE deficient background, adiponectin transgenic apoE deficient mice showed amelioration of atherosclerosis, which was associated with decreased expressions of class A scavenger receptor and tumor necrosis factor alpha. Finally, cDNA encoding adiponectin receptors (AdipoR1 and R2) have been identified by expression cloning, which facilitates the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and R2 as molecular targets.     

The role of the adipocyte hormone adiponectin in cardiovascular disease

Adiponectin, a novel hormone made by fat tissue, regulates energy metabolism and endothelial activation. Serum levels of adiponectin are reduced in conditions that are associated with an increased risk of cardiovascular disease, such as diabetes and the metabolic syndrome. Adiponectin trimers assemble into higher-order oligomers, which have different signaling properties. Adiponectin trimers and a C-terminal globular domain activate AMP-activated protein kinase, whereas hexamer and high-molecular weight isoforms activate nuclear factor-kappa B signaling pathways. Exogenous adiponectin corrects metabolic defects that are associated with insulin resistance, and might protect the endothelium from the progression of cardiovascular disease. Receptors for adiponectin have been described and might provide future therapeutic targets for the treatment of cardiovascular disease.     

脂联素在心血管疾病中的研究进展

脂联素（Adiponectin,APN）是由脂肪细胞分泌的一种血浆蛋白,其血浆中含量丰富,大约为5—30mg／1。目前的研究证实,脂联素在2型糖尿病,冠心病,高血压病中降低,在心力衰竭中显著升高,脂联素水平能预示2型糖尿病和冠心病的发展,并在临床试验中表现出增强胰岛素敏感性、抗动脉粥样硬化、抗炎,预测死亡率等作用,本文就脂联素及其在心血管疾病中的研究进展做一综述。     

Adiponectin as a regulator of vascular redox state: therapeutic implications

Recently, adipose tissue has been implicated in the regulation of vascular function in humans. This regulatory function is mediated via the release of vasoactive cytokines called adipokines. Adiponectin is an adipokine with powerful anti-inflammatory and antioxidant properties being dysregulated in obesity and in insulin resistance states. In both in vitro and in vivo models adiponectin has been shown to increase nitric oxide bioavailability, improve endothelial function, and exert beneficial effects on vascular smooth muscle cell function. Strategies to upregulate adiponectin expression or to potentiate adiponectin signalling may favourably modulate vascular redox state and therefore reduce cardiovascular risk. Various drug classes such as glitazones, newer sulfonylureas, angiotensin receptor blockers, ACE inhibitors and nicotinic acid exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels. Others such as tetrahydrobiopterin or certain antioxidants are also promising in normalizing plasma adiponectin levels. Given the central role of adiponectin in vascular disease states and obesity-related metabolic disorders, improving adiponectin vascular or systemic bioavailability via existing drugs or novel therapeutic strategies may be valuable in the prevention of cardiovascular disease in humans. The discussion of recent patents for the adiponectin as a regulator of vascular redox state also included in this review article.     

A personalized approach to metabolic aspects of obesity

Metabolic syndrome, which is entwined in semantic controversy as to its actual existence as a distinct entity, links several important health conditions with obesity, and more specifically, excessive visceral adiposity. The most common linked disease states include type 2 diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular and coronary heart disease. Much of the controversy surrounding the metabolic syndrome case definition is the purported centrality of insulin resistance as root cause, there being no universally agreed-upon standard for measurement of insulin resistance. Over the past decade, the visceral adipocyte itself has emerged as a key contributor rather than passive bystander in the genesis of the metabolic syndrome. Rather than being a simple storage bin for excess triglyceride, the visceral adipocyte is an active endocrine cell secreting a variety of signal hormones known in the aggregate as adipokines. In optimal health, the predominant recognized adipokine is adiponectin, with downstream insulin-sensitizing, anti-inflammatory, antithrombotic, provasodilatory effects systemically. By contrast, metabolic syndrome is characterized by reduced adiponectin and increased inflammatory adipokine secretion, with downstream effects of insulin resistance, heightened inflammation, prothrombosis, and vasoconstriction. These alternative metabolic states of the adipocyte are characterized in this review as metabolic "yin" and "yang." Lifestyle modifications and drug therapies that promote weight loss, increased physical exercise activity, and increased adiponectin production tend to modulate the system favorably toward metabolic "yin."     

Are decreased AdipoR1 mRNA levels associated with adiponectin resistance in coronary artery disease patients?

The aim of the present study was to investigate if circulating adiponectin levels and the expression of AdipoR1 and AdipoR2 in peripheral blood mononuclear cells (PBMC) are altered in coronary artery disease (CAD) patients, with and without significant stenosis, compared to healthy patients. The present study included 69 patients with presenting symptoms of CAD (26 patients with significant stenosis and 43 patients without significant stenosis). The control group (CG) consisted of 33 healthy patients. Circulating adiponectin levels were measured by enzyme‐linked immunosorbent assay, whereas AdipoR1 and AdipoR2 mRNA levels in PBMC were determined by real‐time polymerase chain reaction. Adiponectin levels were significantly higher in patients with and without significant stenosis compared to the CG (P < 0.001 vs P = 0.006, respectively). Both patient groups had lower AdipoR1 levels compared to the CG (P < 0.001 vs P < 0.001, respectively). There were no significant differences in these parameters between the two patient groups. Adiponectin negatively correlated with body mass index, triglycerides, insulin and homeostasis model assessment of insulin resistance index (HOMA IR), and positively with high‐denisty lipoprotein cholesterol in the CG. Glucose, insulin, and the HOMA IR index negatively correlated with adiponectin in patients. A positive correlation between adiponectin receptors was found in patients and the CG. Decreased AdipoR1 mRNA levels and increased circulating adiponectin in advanced stages of CAD, as well as in patients without significant stenosis, compared to the CG, implies that CAD could be related to ‘adiponectin resistance’. Despite increased adiponectin, its protective effects could be diminished even in early stages of atherosclerosis.     

Autophagy induction: a critical event for the modulation of cell death/survival and inflammatory responses by adipokines

Adipose tissue acts as a dynamic endocrine organ playing critical roles in many metabolic and immune responses. Endocrine functions by adipose tissue are achieved by secretion of diverse cytokines and hormones, collectively called adipokines. Adiponectin and leptin the most abundantly expressed adipokines within adipose tissue have an impact on various physiological responses. While both adiponectin and leptin are secreted from the same location, their physiological functions are not identical. Adiponectin possesses potent anti-inflammatory properties and anti-tumor activities, whereas leptin acts as a pro-inflammatory hormone and generates tumor-promoting effects. Autophagy, a highly conserved intracellular self-digestive process, is implicated in the maintenance of diverse physiological responses. In particular, autophagy plays dual roles in the regulation of cell death/survival (e.g., inducing cell death and cytoprotection) and is associated with anti-inflammatory actions. Increasing recent evidence has indicated that autophagy is implicated in various biological responses by adipokines. Therefore, autophagy would be a promising target for the management of inflammation and tumor growth by adipokines. In this review, we summarize the effects of adiponectin and leptin on autophagy induction and highlight their implications in modulating inflammatory responses and tumor growth.     

Adipokines: therapeutic targets for metabolic syndrome

For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFalpha, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome.     

Effects of chronic acarbose treatment on adipocyte insulin responsiveness, serum levels of leptin and adiponectin and hypothalamic NPY expression in obese diabetic Wistar rats

1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phosphorylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus.     

Adiponectin and cardiovascular disease: mechanisms and new therapeutic approaches

Adiponectin is an abundant plasma protein secreted from adipocytes. Its role in energy homeostasis is well-known, including the regulation of hydrocarbons and lipids metabolism as well as the improvement of insulin resistance. It has been thought to be a key molecule in the development of type 2 diabetes mellitus and metabolic syndrome, which are epidemiological targets for preventing cardiovascular disease. In addition to beneficial metabolic effects, adiponectin seems to have anti-inflammatory, anti-atherosclerotic and vasoprotective actions. Furthermore, adiponectin affects signalling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. The ability of adiponectin to reduce insulin resistance in conjunction with its antiinflammatory and cardioprotective properties makes this adipocytokine a promising therapeutic target. On clinical interest, agents that enhance endogenous adiponectin production or action have potential for the treatment of cardiovascular disease. Management strategies that increase adiponectin levels include weight reduction, Mediterranean diet, thiazolidinediones, antihypertensive and lipid lowering drugs. Current knowledge on the main actions of adiponectin and therapeutic approaches for cardiovascular disease is summarized in this review.     

The Role of Adiponectin in the Skin

Adiponectin (Ad), a 30 kDa molecule, is an anti-diabetic adipokine; although derived from adipose tissue, it performs numerous activities in various other tissues. It binds to its own receptors, namely adiponectin receptor 1(AdipoR1), adiponectin receptor 2 (AdipoR2), and T-cadherin (CDH13). Ad plays several roles, especially as a regulator. It modulates lipid and glucose metabolism and promotes insulin sensitivity. This demonstrates that Ad has a robust correlation with fat metabolism. Furthermore, although Ad is not in direct contact with other tissues, including the skin, it can be delivered to them by diffusion or secretion via the endocrine system. Recently it has been reported that Ad can impact skin cell biology, underscoring its potential as a therapeutic biomarker of skin diseases. In the present review, we have discussed the association between skin cell biology and Ad. To elaborate further, we described the involvement of Ad in the biology of various types of cells in the skin, such as keratinocytes, fibroblasts, melanocytes, and immune cells. Additionally, we postulated that Ad could be employed as a therapeutic target to maintain skin homeostasis.     

Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species (ROS) level and apoptosis. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. In this study, we investigated the protective effects of adiponectin on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by adiponectin treatment. Our results suggest that the protective effects of adiponectin on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that adiponectin may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.     

代谢综合征患者血清脂联素水平与胰岛素抵抗的相关性研究

目的:探讨代谢综合征患者血清脂联素水平与胰岛素抵抗的关系。方法:选取代谢综合征患者35例,另选健康对照组20例,所有实验对象空腹采血离心取血清测定脂联素、胰岛素、血糖、胰岛素敏感性指数、胰岛素抵抗指数。结果:与对照组相比,代谢综合征组血清脂联素水平、胰岛素敏感性指数显著降低(P<0.01),血清胰岛素、血糖显著升高(P<0.01)。在代谢综合征组中,血清脂联素与胰岛素、血糖、胰岛素抵抗指数呈负相关,与胰岛素敏感性指数呈正相关(P<0.05)。结论:低血清脂联素水平与胰岛素抵抗密切相关。     

脂肪因子表达对胰岛素抵抗及代谢综合征的影响

脂肪组织分泌的多种脂肪细胞因子,如肿瘤坏死因子(TNF)-α、白介素(IL)-6、瘦素、脂联素等均可介导或参与慢性炎症反应,导致胰岛素抵抗,进而发展为代谢综合征。在肥胖、炎症-胰岛素抵抗-代谢综合征这一病理生理过程中,脂肪细胞的内分泌调节功能障碍扮演了重要角色。本文综述目前已知的部分脂肪因子与胰岛素抵抗的关系,旨在为肥胖症、糖尿病及代谢综合征发病机制的研究和治疗策略提供线索。     

Down‐regulation of microRNA‐375 regulates adipokines and inhibits inflammatory cytokines by targeting AdipoR2 in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) has been considered as a multi‐factorial metabolic syndrome. MicroRNA‐375 (MiR‐375) was significantly up‐regulated in serum of NAFLD patients and the role of miR‐375 was addressed as a putative biomarker of NAFLD progression. However, the specific function of miR‐375 in the progression of NAFLD is still unclear and the molecular mechanisms underlying NAFLD have yet to be elucidated. Our study aimed at investigating the regulatory role of miR‐375 in the molecular mechanisms of the pathogenic progression of NAFLD and to find out whether miR‐375 regulates the expression level of adipokines and inflammatory cytokines in NAFLD. We found that miR‐375 expression was increased in the serum of high fat diet (HFD)‐feeding mice comparing to that in healthy controls, whereas the expression of Adiponectin receptor 2 (AdipoR2) was decreased in mice fed with HFD. Moreover, inhibiton of miR‐375 up‐regulated the expression of Adiponectin, inhibited the lipid accumulation and down‐regulated both the level of Leptin and inflammatory cytokines including tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 in palmiticacid (PA)‐induced human hepatocellular carcinoma HepG2 cells. In addition, we also found that AdipoR2 was a target of miR‐375 by binding directly to the 3′UTR of it. Of note, the reduced level of TNF‐α, IL‐6 as well as Leptin and the production of Adiponectin by miR‐375 inhibitors was significantly reversed by silencing of AdipoR2 in PA‐induced HepG2 cells. Our findings bring new insight into understanding the complex mechanisms underlying the pathogenesis of NAFLD and provide evidence that miR‐375 might represent a novel therapeutic target for NAFLD.     

Adipokines in inflammation, insulin resistance and cardiovascular disease

1. Obesity is a major determinant of cardiovascular disease (CVD). Studies in the past two decades have shown that adipose tissue is not merely an inert energy reserve of triglycerides, but also an active endocrine organ. 2. Adipose tissue can produce and secrete numerous bioactive peptides and/or proteins termed adipokines. These secretory factors are involved in the regulation of local and systemic inflammation and insulin sensitivity in a paracrine and/or endocrine manner. Inflammation and insulin resistance (IR) play critical roles in the obesity-linked development of CVD, such as atherosclerosis, hypertension and restenosis. 3. In the present minireview, we summarize the relationship between inflammation and IR, as well as their contribution to the development of CVD during adipose tissue dysfunction. In particular, we focus on the effects of various adipokines in pathological processes, which may provide an insight into obesity-linked CVD and facilitate the development of new therapeutic strategies.