脂联素在代谢综合征及心血管疾病中的研究进展

脂联素(APN)由脂肪细胞分泌产生,在代谢综合征和心血管疾病中起重要的保护作用。在肥胖、糖尿病、高血压、冠状动脉硬化性疾病的患者中,APN水平显著降低。APN具有增加胰岛素敏感性、抗炎、抗动脉粥样硬化及保护心肌等作用。本文将对APN及其受体在糖尿病、胰岛素抵抗、代谢综合征及心血管疾病中的作用进行总结概括。     

脂联素调节内质网应激及自噬水平对糖尿病心肌产生保护作用机制的研究进展

我国糖尿病患者居全球首位,其心血管并发症导致死亡十分常见,有效预防和控制糖尿病及心血管并发症非常重要。APN是脂肪细胞分泌的蛋白质,具有抗炎、抗糖尿病和抗动脉粥样硬化的特性,对糖尿病心肌具有保护作用。本文从内质网应激及自噬水平对APN保护糖尿病心肌作用的研究进展进行综述。     

脂联素及T-钙黏蛋白与大鼠糖尿病心肌病的关系

观察糖尿病（DM）大鼠心肌细胞形态学变化,测定血清脂联素（APN）及受体T-钙黏蛋白（T-cad）在心肌的表达水平。DM大鼠心肌细胞超微结构出现符合糖尿病心肌病改变,血清APN及T-cad的表达随着病变发展而升高。血清APN及T-cad的表达均随时间延长增多,从而发挥其保护作用。     

人血浆脂联素分离纯化及活性鉴定

目的: 从人血浆中分离纯化各亚型脂联素(APN),建立人血浆APN活性的检测方法,同时获得制备抗APN各亚型特异性抗体所需的抗原。方法:将-80℃保存的人血浆融解后稀释,采用硫酸铵沉淀、阴离子交换层析和凝胶过滤层析分离纯化人血浆中不同亚型的APN。用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)、免疫印迹（Western blot）和ELISA检测纯化的产物及回收率。通过孵育人脐静脉内皮细胞后,检测磷酸腺苷激活的蛋白激酶（AMPK）的水平反映APN的活性。结果:所获不同亚型的APN均具有生物学活性,高聚体APN激活AMPK的能力最强。APN活性回收率为40%。结论: 建立了一种能够快速、简便从人血浆中分离纯化APN及其亚型并保持其天然的生物学活性的方法,为APN的深入研究奠定了基础。     

进展性脑卒中患者血清脂联素水平检测及其意义

进展性缺血性脑卒中(SIP)占缺血性脑卒中的26％ ～43％[1,2],致残率高,预后差[3],Cnop等[4]临床观察发现脂联素(APN)与致动脉粥样硬化的血脂成分呈负相关,而与对动脉粥样硬化有保护作用的血脂成分呈正相关.也有人认为脑梗死患者的APN水平同其神经功能评分、梗死灶体积及颈动脉狭窄程度呈负相关[5].本文探讨SIP患者血清ANP水平及意义.     

Adiponectin通过FoxO1信号通路减轻阿霉素细胞毒性的作用机制研究

目的 阐明FoxO1在脂联素(Adiponectin,APN)减轻阿霉素(Doxorubicin,DOX)心肌细胞毒性中的作用及机制.方法 将分离的乳鼠心肌原代细胞(Neonatal rat cardiomyocytes,nrCMs)随机分为对照组(CON)、APN处理组(APN)、DOX损伤组(DOX)、APN保护组...     

脂联素与缺血性卒中

脂联素(adiponectin,APN)是脂肪组织分泌的一种具有保护作用的胰岛素敏感性蛋白质,具有调节糖脂代谢、保护血管内皮功能、促进血管新生、抗炎等作用,在脑血管病中发挥着重要的保护作用.文章对APN及其在缺血性卒中中的作用进行了综述.     

脂联素和胰岛素抵抗、2型糖尿病研究进展

研究证实脂联素(APN)有胰岛素增敏作用，能拮抗胰岛素抵抗。血浆APN的降低是发生胰岛素抵抗和糖尿病的独立危险因素。APN的胰岛素增敏作用是通过增加骨骼肌脂肪酸氧化以及抑制肝糖异生实现的。另外，APN基因多态性可引起APN生成和分泌的减少，也是导致胰岛素抵抗和糖尿病的原因之一。对APN的研究将为探讨胰岛素抵抗和2型糖尿病的发病机制及治疗方案提供新的线索。     

抗TNF-α中和抗体通过升高脂联素水平减轻小鼠心肌缺血/再灌注损伤的作用

目的:阐明心肌缺血/再灌注(MI/R)时,脂联素(APN)与肿瘤坏死因子-α(TNF-α)的关系,以及使用中和抗体阻断TNF-α可否提高血浆APN,进而发挥心肌保护作用。方法: 96只成年雄性C57小鼠和36只ob/ob小鼠均采用30 min缺血/再灌注(I/R)建立MI/R模型。96只C57小鼠分为假手术组、手术+盐水对照组及手术+抗TNF-α中和抗体治疗组(n=32);36只ob/ob小鼠分为ob/ob假手术组、ob/ob手术+盐水对照组及ob/ob手术+抗TNF-α中和抗体治疗组(n=12)。假手术或缺血20 min后,腹腔注射给予单次抗TNF-α中和抗体或盐水干预。分别采用ELISA检测TNF-α与APN血浆水平;小鼠心脏超声评估心脏LVEF;伊文氏蓝/TTC染色检测心脏梗死面积;以及TUNEL/Caspase-3活性检测观察心肌细胞凋亡。结果: 血浆ELISA测定发现,MI/R后,小鼠血浆TNF-α水平在再灌后1 h即显著升高,后缓慢下降。注射抗TNF-α中和抗体可在再灌后1 h即中和TNF-α（P<0.01）,同时在再灌注3 h、8 h、1 d及3 d后4个时间点,较给予盐水对照显著升高血浆APN（P<0.01）。通过小鼠心脏超声、伊文氏蓝/TTC染色和TUNEL/Caspase-3活性检测发现,与给予盐水的对照相比,腹腔注射抗TNF-α中和抗体可提高小鼠的心肌功能（P<0.05）、减少梗死面积（P<0.01）及心肌细胞的凋亡（P<0.01）。而在ob/ob小鼠中,通过以同样的实验方法证实,单次注射抗TNF-α中和抗体已不能提高血浆APN的含量,其减轻心肌损伤的作用同样被显著削弱,但给予APN球状片段仍可发挥心肌保护作用。结论: 以抗TNF-α的中和抗体阻断TNF-α可逆转MI/R后血浆APN的降低并发挥心肌保护作用,提示抗TNF-α中和抗体发挥的心肌保护作用可能部分通过提高APN实现。     

腹部脂肪CT定量参数联合脂联素/瘦素比值对非酒精性脂肪性肝病严重程度的评估价值

目的:探究腹部脂肪CT定量参数联合脂联素(APN)/瘦素(LP)比值对非酒精性脂肪性肝病(NAFLD)严重程度的评估价值。方法:选取2018年3月至2021年7月收治的83例NAFLD患者，按肝脾CT值比值将其分为轻度组(n=50)、中重度组(n=33),并纳入同期83例健康者为对照组。比较两组患者临床资料、CT定量参数及血清APN、LP水平、APN/LP比值；分析NAFLD患者CT定量参数、APN/LP比值与临床资料的相关性；比较不同严重程度的NAFLD患者CT定量参数、APN/LP比值；评估CT定量参数、APN/LP比值诊断中重度NAFLD的价值。结果:NAFLD组患者甘油三酯(TG)、体重指数(BMI)、丙氨酸氨基转移酶(ALT)、总胆固醇(TC)、天门冬氨酸氨基转移酶(AST)、内脏脂肪面积(VFA)、矢状径、总脂肪面积(TFA)、横径、腰围及血清LP水平均高于对照组(P<0.05),血清APN水平及APN/LP比值低于对照组(P<0.05);NAFLD患者VFA、APN/LP比值均与TG、BMI、ALT相关(P<0.05);中重度组NAFLD患者VFA、矢状...     

脂联素与慢性肝病研究进展

脂联素(adiponectin)是脂肪细胞因子家族的重要成员之一,具有增强胰岛素敏感性、抗炎、抗动脉粥样硬化及负性调节免疫功能等多种作用。随着对脂联素研究的深入,发现其与慢性肝病的发生密切相关。文章就脂联素的来源、结构、生物学功能及其在慢性肝病中的表达情况和其在慢性肝病治疗中的潜在效应作一综述。     

Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)-granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units-erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor alpha. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions. (Blood. 2000;96:1723-1732)     

Adiponectin action from head to toe

Adiponectin, the most abundant protein secreted by white adipose tissue, is known for its involvement in obesity-related disorders such as insulin resistance, type 2 diabetes mellitus and atherosclerosis. Moreover, modulation of the circulating adiponectin concentration is observed in pathologies that are more or less obesity-related, such as cancer and rheumatoid arthritis. The wide distribution of adiponectin receptors in various organs and tissues suggests that adiponectin has pleiotropic effects on numerous physiological processes. Besides its well-known insulin-sensitizing, anti-inflammatory and antiatherosclerotic properties, accumulating evidence suggests that adiponectin may also have anticancer properties and be cardioprotective. A beneficial effect of adiponectin on female reproductive function was also suggested. Since adiponectin has numerous beneficial biological functions, its use as a therapeutic agent has been suggested. However, the use of adiponectin or its receptors as therapeutic targets is complicated by the presence of different adiponectin oligomeric isoforms and production sites, by multiple receptors with differing affinities for adiponectin isoforms, and by cell-type-specific effects in different tissues. In this review, we discuss the known and potential roles of adiponectin in various tissues and pathologies. The therapeutic promise of administration of adiponectin and the use of its circulating levels as a diagnostic biomarker are further discussed based on the latest experimental studies.     

Altered Molecular Weight Forms of Adiponectin in Hypertension

An important link between adiponectin and hypertension has been proposed in clinical studies. In the circulation, adiponectin is predominantly present in multimeric complexes, of which high–molecular weight (HMW) adiponectin is thought to represent the biological active form. The authors investigated which role the different multimeric adiponectin isoforms play in context with hypertension as compared to total adiponectin levels. Fifty (19 normotensive/31 hypertensive) patients were included in the study. Total adiponectin and adiponectin multimers were determined by enzyme-linked immunosorbent assay and western blot. The authors analyzed associations between adiponectin multimer levels and blood pressure. Total adiponectin concentrations were not significantly different between hypertensive and normotensive patients (6.8±2.3 vs 7.5±4.2 μg/mL). HMW adiponectin was significantly lower (P< .05) and low–molecular weight adiponectin was significantly higher ( P< .01) in hypertensive than in normotensive persons (3.8±1.7 vs 5.2±3.0 μg/mL and 0.9±0.5 vs 1.8±0.9, respectively). Low molecular weight was an independent predictor for the presence of hypertension (effect coefficient: 0.160–0.445; P< .001) in multivariate analyses. These results suggest that the composition of the molecular weight forms of adiponectin in hypertension are characterized by reduced HMW adiponectin, the proposed major active form of adiponectin, and increased low–molecular weight adiponectin. Moreover, the latter represents an independent predictor of prevalent hypertension, suggesting an association between adiponectin multimer composition and hypertension.     

Adiponectin and energy homeostasis

White adipose tissue (WAT) is the premier energy depot. Since the discovery of the hormonal properties of adipose-secreted proteins such as leptin and adiponectin, WAT has been classified as an endocrine organ. Although many regulatory effects of the adipocyte-derived hormones on various biological systems have been identified, maintaining systemic energy homeostasis is still the essential function of most adipocyte-derived hormones. Adiponectin is one adipocyte-derived hormone and well known for its effect in improving insulin sensitivity in liver and skeletal muscle. Unlike most other adipocyte-derived hormones, adiponectin gene expression and blood concentration are inversely associated with adiposity. Interestingly, recent studies have demonstrated that, in addition to its insulin sensitizing effects, adiponectin plays an important role in maintaining energy homeostasis. In this review, we summarize the progress of research about 1) the causal relationship of adiposity, energy intake, and adiponectin gene expression; and 2) the regulatory role of adiponectin in systemic energy metabolism.     

Effect of adiponectin on murine colitis induced by dextran sulfate sodium

BACKGROUND & AIMS: Adiponectin, an adipose tissue-derived hormone, exhibits anti-inflammatory properties and has various biological functions, such as increasing insulin sensitivity, reducing hypertension, and suppressing atherosclerosis, liver fibrosis, and tumor growth. The aim of the present study was to determine the effect of adiponectin on intestinal inflammation. METHODS: We investigated the effect of adiponectin on dextran sulfate sodium (DSS)-induced colitis by using adiponectin-knockout (APN-KO) mice and an adenovirus-mediated adiponectin expression system. We also examined the contribution of adiponectin deficiency to trinitrobenzene sulfonic acid (TNBS)-induced colitis. In vitro, we examined the effect of adiponectin on intestinal epithelial cells. RESULTS: After administration of 0.5% DSS for 15 days, APN-KO mice developed much more severe colitis compared with wild-type mice. The messenger RNA expression levels of chemokines were significantly higher in the colonic tissues of DSS-treated APN-KO mice compared with wild-type mice, accompanied by increased cellular infiltration, including macrophages. Adenovirus-mediated supplementation of adiponectin significantly attenuated the severity of colitis, but there were no differences in the severity of TNBS-induced colitis between the 2 groups. Adiponectin receptors were expressed in intestinal epithelial cells, and adiponectin inhibited lipopolysaccharide-induced interleukin-8 production in intestinal epithelial cells. CONCLUSIONS: Adiponectin is protective against DSS-induced murine colitis, probably due to the inhibition of chemokine production in intestinal epithelial cells and the following inflammatory responses, including infiltration of macrophages and release of proinflammatory cytokines.     

Serum concentrations of high-molecular weight adiponectin and their association with sex steroids in premenopausal women

At present, the association between adiponectin and sex hormones in women is controversial. Recent studies suggest that it is high-molecular weight (HMW) adiponectin and the HMW to total adiponectin ratio rather than total adiponectin that are associated with antiatherogenic activities, insulin sensitivity, metabolic syndrome, and prediction of cardiovascular events. The present study aimed to investigate whether measuring HMW adiponectin and the HMW to total adiponectin ratio rather than total adiponectin might be more useful to detect an association between circulating female sex steroids and adipocytokines. In a clinical trial, we investigated the associations of total adiponectin, HMW adiponectin, and the HMW to adiponectin ratio with several androgens and estradiol in 36 healthy premenopausal women with regular cycles. No association between the investigated sex hormones and adiponectin was observed. The HMW adiponectin was negatively correlated with estradiol after adjustment for age and body mass index. The HMW to total adiponectin ratio was significantly negatively associated with testosterone, free testosterone, and androstenedione. The testosterone to estradiol ratio, as a parameter for the estrogen-androgen balance, was not associated with adiponectin or the HMW isoform. In conclusion, there is a negative association between estradiol and HMW adiponectin, and between testosterone, free testosterone, and androstenedione and the HMW to adiponectin ratio. Thus, one mechanism whereby female sex steroids may influence the cardiovascular risk of women could be alteration of the relationship between HMW and total adiponectin concentrations in plasma.     

T-钙粘蛋白——一种新的脂联素受体

脂联素(ADP)是来源于脂肪组织的细胞因子,具有抗炎、抗动脉粥样硬化、防止动脉内膜中层增厚和增加胰岛素敏感性的作用。脂联素的这些效用必须通过脂联素受体(AdipoR)的介导方能实现。T-钙粘蛋白的组织分布非常广泛,在心血管系统高表达,在肌肉组织低表达。T-钙粘蛋白是脂联素六聚体和高分子质量多聚体的受体,其与脂联素球形结构域、脂联素三聚体都不能结合。T-钙粘蛋白在活体内可诱导血管增殖。T-钙粘蛋白亦有抑制血管内膜增生、阻止动脉粥样硬化发展、抑制肝脏糖异生的作用。     

Globular adiponectin improves high glucose-suppressed endothelial progenitor cell function through endothelial nitric oxide synthase dependent mechanisms

Plasma levels of adiponectin, an adipose-specific protein with putative anti-atherogenic properties, could be down-regulated in obese and diabetic subjects. Recent insights suggest that the injured endothelial monolayer is regenerated by circulating endothelial progenitor cells (EPCs), but high glucose reduces number and functions of EPCs. Here, we tested the hypothesis that globular adiponectin can improve high glucose-suppressed EPC functions by restoration of endothelial nitric oxide synthase (eNOS) activity. Late EPCs isolated from healthy subjects appeared with cobblestone shape at 2-4 weeks. EPCs were incubated with high glucose (25 mM) and treatment with globular adiponectin for functional study. Migration and tube formation assays were used to evaluate the vasculogenetic capacity of EPCs. The activities of eNOS, Akt and concentrations of nitric oxide (NO) were also determined. Administration of globular adiponectin at physiological concentrations promoted EPC migration and tube formation, and dose-dependently upregulated phosphorylation of eNOS, Akt and augmented NO production. Chronic incubation of EPCs in high-glucose medium significantly impaired EPC function and induced cellular senescence, but these suppression effects were reversed by treatment with globular adiponectin. Globular adiponectin reversed high glucose-impaired EPC functions through NO- and p38 MAPK-related mechanisms. In addition, nude mice that received EPCs treated with adiponectin in high glucose medium showed a significant improvement in blood flow than those received normal saline and EPCs incubated in high glucose conditions. The administration of globular adiponectin improved high glucose-impaired EPC functions in vasculogenesis by restoration of eNOS activity. These beneficial effects may provide some novel rational to the vascular protective properties of adiponectin.     

Serum adiponectin level as an independent predictor of mortality in patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with altered energy homeostasis and myocardial inflammation, hypertrophy, and fibrosis. Adiponectin, an insulin-sensitizing adipocytokine, may affect these pathogenic factors, and the circulating adiponectin level may serve as a biological marker of CHF. This study aimed to assess the significance of serum adiponectin as a prognostic marker for Japanese CHF patients. METHODS AND RESULTS: The serum adiponectin levels were compared between 54 (24 ischemic and 30 non-ischemic) CHF patients with left ventricular systolic dysfunction and 55 age- and gender-matched control subjects. The CHF patients also underwent simultaneous clinical assessment and measurements for brain natriuretic peptide (BNP) and parameters of lipid or glucose metabolism. Compared with the controls, the CHF patients showed significantly increased serum adiponectin levels [6.7 (4.9-12.6) vs 14.6 (9.7-25.4) microg/ml, p<0.0001]. In the CHF patients, the log-transformed values of the serum adiponectin levels positively correlated with the log-transformed values of the plasma BNP levels (p=0.0003, r=0.48) and inversely correlated with the body mass index (p=0.0006, r=-0.46). Furthermore, an increase in the serum adiponectin level was associated with higher mortality (p<0.05), particularly in the ischemic CHF patients (p<0.005). CONCLUSIONS: An increase in the circulating adiponectin level was associated with higher mortality in the ischemic CHF patients. Adiponectin may be an informative risk marker for Japanese CHF patients.