Increase in visfatin after weight loss induced by gastroplastic surgery

Objective: The recently described adipokine visfatin is produced in visceral fat and has been suggested to influence insulin resistance. To investigate whether visfatin concentrations are related to changes in body weight, this adipokine was measured in insulin‐resistant severely obese patients before and after gastroplastic surgery. Research Methods and Procedures: Visfatin, interleukin‐6, high‐sensitivity C‐reactive protein, homeostasis model assessment of insulin resistance (HOMA‐IR), and other clinical parameters were assessed in 36 severely obese subjects (28 female; mean age, 43 years) with a median BMI of 44.3 kg/m² (95% confidence interval, 43.3 to 48.1 kg/m²). Results: After surgery, BMI decreased to a median of 31.9 kg/m² (30.1 to 35.1 kg/m²) (p < 0.0001). Median visfatin concentrations increased significantly after weight loss [70.9 ng/mL (61.4 to 75.6 ng/mL) vs. 86.4 ng/mL (79.4 to 89.8 ng/mL); p < 0.0005]. This increase correlated with the decrease of insulin and HOMA‐IR and was associated with a reduction in plasma interleukin‐6 and high‐sensitivity C‐reactive protein concentrations. Discussion: Massive weight loss after gastroplastic surgery is accompanied by an increase in circulating concentrations of the novel adipokine visfatin. This increase correlates with the decrease in plasma insulin concentrations and HOMA‐IR.     

The novel adipocytokine visfatin exerts direct cardioprotective effects

Visfatin is an adipocytokine capable of mimicking the glucose-lowering effects of insulin and activating the pro-survival kinases phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)-extracellular signal-regulated kinase 1 and 2 (Erk 1/2). Experimental studies have demonstrated that the activation of these kinases confers cardioprotection through the inhibition of the mitochondrial permeability transition pore (mPTP). Whether visfatin is capable of exerting direct cardioprotective effects through these mechanisms is unknown and is the subject of the current study. Anaesthetized C57BL/6 male mice were subjected to in situ 30 min. of regional myocardial ischaemia and 120 min. of reperfusion. The administration of an intravenous bolus of visfatin (5 x 10(-6) micromol) at the time of myocardial reperfusion reduced the myocardial infarct size from 46.1+/-4.1% in control hearts to 27.3+/-4.0% (n>or= 6/group, P<0.05), an effect that was blocked by the PI3K inhibitor, wortmannin, and the MEK1/2 inhibitor, U0126 (48.8+/-5.5% and 45.9+/-8.4%, respectively, versus 27.3+/-4.0% with visfatin; n>or= 6/group, P<0.05). In murine ventricular cardiomyocytes subjected to 30 min. of hypoxia followed by 30 min. of reoxygenation, visfatin (100 ng/ml), administered at the time of reoxygenation, reduced the cell death from 65.2+/-4.6% in control to 49.2+/-3.7%(n>200 cells/group, P<0.05), an effect that was abrogated by wortmannin and U0126 (68.1+/-5.2% and 59.7+/-6.2%, respectively; n>200 cells/group, P>0.05). Finally, the treatment of murine ventricular cardiomyocytes with visfatin (100 ng/ml) delayed the opening of the mPTP induced by oxidative stress from 81.2+/-4 sec. in control to 120+/-7 sec. (n>20 cells/group, P<0.05) in a PI3K- and MEK1/2-dependent manner. We report that the adipocytokine, visfatin, is capable of reducing myocardial injury when administered at the time of myocardial reperfusion in both the in situ murine heart and the isolated murine cardiomyocytes. The mechanism appears to involve the PI3K and MEK1/2 pathways and the mPTP.     

Can adipokines serum levels be used as biomarkers of hand osteoarthritis?

Purpose: To evaluate serum levels of visfatin, resistin and adiponectin in patients with erosive (E) and non-erosive (NE) osteoarthritis (OA) of the hand (HOA) compared to normal controls (NC).

Methods: 94 outpatients with E HOA and NE HOA and 21 NC were enrolled. The radiological assessment of both hands was performed according to the Kellgren–Lawrence and Kallman score. Patients were divided into two subsets (lone HOA or generalized OA) based on clinically OA involvement of knee and hip. Serum visfatin, resistin and adiponectin levels were determined by ELISA assay.

Results: Visfatin was significantly higher in E HOA patients in comparison to NC and NE HOA group. Resistin showed a significant increase in both E HOA and NE HOA groups versus NC, in particular in generalized OA. No significant differences among groups were found in adiponectin. The Kallman score was more severe in the two subsets of E HOA patients compared to NE HOA.

Conclusions: This study showed increased levels of resistin in erosive and non-erosive HOA, and higher visfatin levels in E HOA in comparison to NE HOA. These data suggest the adipokines possible role in the pathogenesis of HOA and their potential usefulness as biomarkers of the disease.     

非神经元型胆碱能系统在（前）脂肪细胞的表达及nAChRα7功能状态对前脂肪细胞Visfatin基因表达的影响

原核生物、真核生物、植物体的非神经细胞和组织中,尤其是多种免疫活性细胞中,均证实乙酰胆碱酯酶（acetylcholinesterase,AChE）、胆碱乙酰转移酶（choline acetyltransferase,ChAT）和乙酰胆碱受体（acetylcholine receptor, AChR）各亚型在内的胆碱能系统组分的存在,其中烟碱样乙酰胆碱受体α7（nicotinic acetylcholine receptor α7,nAChRα7）是烟碱样胆碱能抗炎通路（nicotinic anti-inflammatory pathway）中重要的分子核心机制,同时也是机体限制宿主防御反应扩大的内源性抗炎机制之一. 本文旨在探讨（前）脂肪细胞上非神经元型胆碱能系统是否存在及初步揭示烟碱样胆碱能受体α7对前脂肪细胞功能的影响. 以体外培养的3T3-L1前脂肪细胞为研究对象,采用免疫组化和蛋白质免疫印迹技术,分别检测前脂肪细胞和成熟脂肪细胞中乙酰胆碱酯酶、胆碱乙酰转移酶和烟碱样乙酰胆碱受体α7的3种胆碱能系统主要组分的蛋白表达. 另将前脂肪细胞分为给予广谱烟碱样乙酰胆碱受体激动剂尼古丁、特异性烟碱样乙酰胆碱受体α7激动剂氯化胆碱及特异性烟碱样乙酰胆碱受体α7拮抗剂甲基牛扁亭碱干预12 h、24 h、36 h,并设立相应处理时间的空白对照组,逆转录聚合酶链反应检测前脂肪细胞visfatin mRNA表达情况. 免疫组化染色可见前脂肪细胞中AChE、ChAT及AChRα7均有阳性表达;蛋白免疫印迹检测进一步半定量证实了前脂肪细胞和成熟脂肪细胞中AChE、ChAT及AChRα7的蛋白表达;拮抗剂甲基牛扁亭碱(10⁶～10⁴mol/L)时间、剂量依赖性上调前脂肪细胞visfatin mRNA表达(1.3～1.55fold,P<0.01),与对应空白对照组相比,存在显著性统计学差异; 加入不同剂量的尼古丁和氯化胆碱,则前脂肪细胞中visfatin mRNA表达水平与对应空白对照组相比,均不同程度地下降,其中以氯化胆碱的抑制效应更为显著. 前脂肪细胞与成熟脂肪细胞中均存在有独立的胆碱能体系,其中AChRα7很可能在调节脂肪细胞因子分泌及肥胖相关的病理生理过程中发挥重要作用.     

Circulating visfatin levels and cancers risk: A systematic review and meta-analysis

Visfatin levels have been reported to be abnormal in many types of cancers. However, epidemiological studies yielded inconsistent results. Therefore, a meta-analysis was performed to assess the association between circulating visfatin levels and cancer risk. A systematic search was conducted for relevant studies in health-related electronic databases up to March 2018. Data related to standard mean difference (SMD) and overall odds ratio (ORS) were collected and analyzed. Summary SMD and pooled OR with 95% CIs were calculated using a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. A total of 27 studies with 2,693 cases and 3,040 healthy controls were included in meta-analysis for pooling SMD analysis. The results of the meta-analysis showed a significant higher visfatin levels in patients with various cancers than in controls, with a pooled SMD of 0.88, 95% CI = 0.56–1.20, p = 0.000. In subgroup, metaregression, Galbraith plot, and sensitivity analysis showed no substantial difference among all the analyzed factors. Data from 14 studies were also used for pooling ORs analysis. Metaresults revealed that high visfatin levels were associated with cancer risk (OR = 1.24, 95% CI: 1.14–1.34, p = 0.000). No evidence of publication bias was observed for pooling ORs and SMD analysis. This meta-analysis indicated a significant association between high circulating visfatin levels and increased risk of various cancers. Visfatin may represent a potential biomarker for early detection of cancers who may benefit from preventive treatment.Note.     

Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma

High plasma levels of nicotinamide phosphoribosyltransferase (NAMPT), traditionally considered an intracellular enzyme with a key role in NAD synthesis, have been reported in several oncological, inflammatory and metabolic diseases. We now show that eNAMPT can be actively released by melanoma cells in vitro. We analysed the mechanisms of its release, and we found both classical and non‐classical pathway involvement. eNAMPT released by melanoma cells, in our hands, has paracrine and autocrine effects: it activates MAPK, AKT and NF‐κB pathways and increases colony formation in anchorage‐independent conditions. eNAMPT also induces M1 polarization in human monocytes. Last, we demonstrate, for the first time in any cancer type, that eNAMPT levels in plasma of tumour‐bearing mice increase and that this increase can be reconducted to the tumour itself. This provides an important cue on previous observations that eNAMPT is increased in patients with cancer. Moreover, silencing NAMPT in melanoma cells leads to a reduction in the tumour growth rate. Our findings extend the basis to consider eNAMPT as a cytokine involved in tumour progression.     

Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter‐endothelial junction disruption: role of HMGB1

Recent studies have indicated that the inflammasome plays a critical role in the pathogenesis of vascular diseases. However, the pathological relevance of this inflammasome activation, particularly in vascular cells, remains largely unknown. Here, we investigated the role of endothelial (Nucleotide‐binding Oligomerization Domain) NOD‐like receptor family pyrin domain containing three (Nlrp3) inflammasomes in modulating inter‐endothelial junction proteins, which are associated with endothelial barrier dysfunction, an early onset of obesity‐associated endothelial injury. Our findings demonstrate that the activation of Nlrp3 inflammasome by visfatin markedly decreased the expression of inter‐endothelial junction proteins including tight junction proteins ZO‐1, ZO‐2 and occludin, and adherens junction protein VE‐cadherin in cultured mouse vascular endothelial (VE) cell monolayers. Such visfatin‐induced down‐regulation of junction proteins in endothelial cells was attributed to high mobility group box protein 1 (HMGB1) release derived from endothelial inflammasome‐dependent caspase‐1 activity. Similarly, in the coronary arteries of wild‐type mice, high‐fat diet (HFD) treatment caused a down‐regulation of inter‐endothelial junction proteins ZO‐1, ZO‐2, occludin and VE‐cadherin, which was accompanied with enhanced inflammasome activation and HMGB1 expression in the endothelium as well as transmigration of CD43⁺ T cells into the coronary arterial wall. In contrast, all these HFD‐induced alterations in coronary arteries were prevented in mice with Nlrp3 gene deletion. Taken together, these data strongly suggest that the activation of endothelial Nlrp3 inflammasomes as a result of the increased actions of injurious adipokines such as visfatin produces HMGB1, which act in paracrine or autocrine fashion to disrupt inter‐endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders such as obesity or high‐fat/cholesterol diet.     

A visfatin promoter polymorphism is associated with low-grade inflammation and type 2 diabetes

Visfatin (also known as pre-B cell colony-enhancing factor, or PBEF) is a pro-inflammatory adipokine expressed predominantly in visceral fat. We investigated whether polymorphisms at the visfatin/PBEF locus influence the risk of type 2 diabetes (T2D). Linkage disequilibrium analysis of 52 single nucleotide polymorphisms spanning the entire gene (34.7 kb) plus 20.5 kb of the upstream region and 25.5 kb of the downstream region revealed a single haplotype block that could be tagged by seven single nucleotide polymorphisms. These seven tags were typed in a group of T2D patients (n = 814) and a group of non-diabetic controls (n = 320) of white origin. A significant association was observed at -948C>A, with minor allele frequencies of 0.157 in T2D cases and 0.119 in non-diabetic controls (p = 0.021). In a non-diabetic population (n = 630), the same -948 allele that conferred increased risk of T2D was significantly associated with higher plasma levels of fibrinogen and C-reactive protein (p = 0.0022 and 0.0038, respectively). However, no significant associations were observed with BMI, waist circumference, serum glucose levels, or fasting insulin levels. Our findings suggest that the visfatin/PBEF gene may play a role in determining T2D susceptibility, possibly by modulating chronic, low-grade inflammatory responses.     

Visfatin,一种新的脂肪因子

visfatin是新近发现的主要由人和小鼠内脏脂肪组织分泌的一种脂肪细胞因子,其结构与pre-B细胞集落增强因子相似。它能够发挥类似胰岛素的作用,与Ⅱ型糖尿病相关联,降低血糖,促进糖摄取,可结合并活化胰岛素受体,激活胰岛素信号通路。Visfatin与肥胖密切相关并能够促进脂肪细胞的分化,还能促进血管平滑肌细胞成熟。Visfatin的表达受炎症反应因子和多种激素的调节。Visfatin可能是联系机体糖脂代谢的重要分子,它的发现可为揭示糖尿病与肥胖的发生发展机制提供新的研究思路,为代谢综合征的治疗提供新方案。     

脂肪因子visfatin的调节与功能多样性

内脏脂肪素(visfatin)是一种由内脏脂肪细胞分泌的分子质量为52 ku的蛋白质细胞因子．基因序列分析显示其cDNA编码序列与前B细胞集落增强因子(PBEF)同源且在进化中高度保守．Visfatin被发现具有多种迥然不同的生物活性：通过与胰岛素受体相互作用,在不同的情况下visfatin可表现出类胰岛素或抗胰岛素样作用;在细胞质中,visfatin具有烟酰胺磷酸核糖转移酶(Nampt)活性,能够催化烟酰胺腺嘌呤二核苷酸(NAD)的生物合成;作为分泌型的细胞因子,visfatin还可以诱导多种炎性因子的表达,如TNFα、IL-1β和IL-6．Visfatin与一些代谢疾病和急、慢性炎性疾病的关系日益受到重视,如糖尿病、肥胖、急性肺损伤、类风湿性关节炎、败血症、心肌梗塞和炎性肠病等．最近,对visfatin的启动子区及其单核苷酸多态性(SNP)的研究,进一步深化了人们对其在疾病发病机制中作用的认识．重点讨论visfatin的结构、功能多态性以及它与多种疾病的关系．