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。     

PBEF/Nampt/Visfatin——脂肪因子、蛋白酶、炎症因子?

脂肪因子是由脂肪组织分泌的肽类物质,影响着整个机体的能量代谢,在多种病理过程中起着关键性调节作用。PBEF/Nampt/Visfatin是2005日本学者新发现的一种脂肪因子,由于其具有类胰岛素作用而成为研究热点。目前对该因子属性、作用及作用机制的探讨十分激烈。尽管对PBEF/Nampt/Visfatin的认识尚未明了,但其在代谢性疾病中的作用为该类疾病的病理机制做了重要补充,并且为攻克这类疾病提供了新思路、新靶点。     

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．     

硫辛酸在糖尿病微血管病变治疗中的作用

糖尿病是危害人群健康的一种慢性疾病。糖尿病微血管病变是糖尿病的特异性病变,其并发症主要包括肾脏病变,视网膜病变及神经病变。而其发生受多种因素影响,其发生机制研究已形成多种学说,主要有非酶糖基化、多元醇通路、氧化应激及己糖胺通路学说等。近年来硫辛酸对糖尿病微血管并发症的治疗作用是国内外研究的热点,硫辛酸是高效抗氧化剂,清除自由基和活性氧,再生体内谷胱甘肽等其他抗氧化剂,减弱氧化应激,从而硫辛酸可减弱多种糖尿病微血管并发症的诱发因素,并干预多元醇通路与己糖胺通路,对糖尿病微血管并发症中的相应靶器官有保护作用,本文就硫辛酸在糖尿病微血管病变中的应用做一简要综述。     

COX-2与糖尿病并发症关系研究进展

糖尿病是一种慢性、低度炎症性疾病。多种因素刺激下,环氧化酶COX-2在胰岛及多种组织中高水平表达。它通过与炎症因子和炎症介质,如一氧化氮、核因子-κB、前列腺素E等相互作用,对相应组织产生作用,从而促进了糖尿病并发症的发生和发展。对COX-2的研究可进一步揭示糖尿病并发症发生的分子机制,为预防和治疗糖尿病并发症提供新的思路。     

妊娠期糖尿病患者糖化白蛋白、内脂素、摄食抑制因子-1水平与胰岛素抵抗和妊娠结局的关系分析

摘要 目的：观察妊娠期糖尿病（GDM）患者糖化白蛋白（GA）、内脂素（Visfatin）、摄食抑制因子-1（Nesfatin-1）水平与胰岛素抵抗的关系,并分析导致妊娠结局不良的危险因素。方法：选取2018年6月~2021年1月期间我院收治的120例GDM患者作为观察组,同一时间段选择来我院行孕检的90例正常孕妇作为对照组。检测受试者血清中Visfatin、Nesfatin-1、GA、空腹胰岛素（FINS）、空腹血糖（FPG）水平,计算胰岛素抵抗指数（HOMA-IR）、胰岛β细胞功能指数（HOMA-β）。采用Pearson相关分析Visfatin、Nesfatin-1、GA与胰岛素抵抗的关系。采用多因素Logistic回归分析妊娠结局不良的影响因素。结果：观察组的GA、Visfatin、Nesfatin-1、HOMA-IR高于对照组,HOMA-β低于对照组（P<0.05）。Pearson相关分析结果显示,GA、Visfatin、Nesfatin-1与HOMA-β呈负相关,而与HOMA-IR呈正相关（P<0.05）。观察组的妊娠不良结局发生率明显高于对照组（P<0.05）。单因素分析结果显示：妊娠不良结局与分娩年龄、居住地、糖尿病家族史、产前体质量指数（BMI）、合并多囊卵巢综合征、流产史、分娩史、甲状腺功能情况、产次、FPG、FINS、GA、Visfatin、Nesfatin-1、HOMA-IR、HOMA-β有关（P<0.05）,而与文化程度、单/双胎妊娠、孕次无关（P>0.05）。Logistic回归分析结果显示：居住地为城市、产前BMI≥28 kg/m²、分娩年龄≥35岁、合并多囊卵巢综合征、GA≥13%、Visfatin≥82mmol/L、Nesfatin-1≥9 μg/L、流产史、甲状腺功能异常是导致GDM产妇妊娠结局不良的危险因素（P＜0.05）。结论：GDM患者中存在GA、Visfatin、Nesfatin-1高表达,且与胰岛素抵抗明显相关。GDM产妇的妊娠不良结局发生率较高,受分娩年龄、居住地、产前BMI、合并多囊卵巢综合征、流产史、GA、Visfatin、Nesfatin-1、甲状腺功能异常等多种因素影响,可考虑针对上述患者采取相关干预措施,以改善患者的妊娠结局。     

新型脂肪因子visfatin的生物学意义

Visfatin是腹部内脏脂肪组织高表达的一种生物活性小分子,能够调控腹部脂肪细胞的分化和成脂作用,并能与胰岛素受体结合,调节胰岛素敏感性。Visfatin的发现及其类胰岛素生物活性,引发人们对体内糖脂代谢平衡、脂肪细胞分化与增殖的重新认识。     

Vaspin与动脉粥样硬化的研究进展

内脏脂肪组织特异性丝氨酸蛋白酶抑制物(Vaspin)是新发现的脂肪因子,主要由内脏脂肪组织产生,它的分泌和表达受多种因素的影响,并与肥胖、2型糖尿病、动脉粥样硬化(Atherosclerosis,As)等有关。Vaspin具有胰岛素增敏性、改善糖耐量、抑制血管炎症反应等作用,对这些作用机制的认识,能为防治动脉粥样硬化提供新的治疗靶点。     

抵抗素基因表达的调控因素

抵抗素是一种主要由脂肪组织分泌的多肽类激素。它与肥胖、2型糖尿病、胰岛素抵抗等疾病具有相关性,并受多种因素调控。胰岛素和抗糖尿病药物、激素、细胞因子、神经递质、营养与饮食等都参与抵抗素基因表达的调控。对抵抗素的深入研究将有助于了解胰岛素抵抗相关疾病的发病机制,为糖尿病、肥胖等的防治提供实验基础。     

Visfatin在非酒精性脂肪性肝病发展过程中的表达及意义

观察血清及肝脏组织中内脂素(Visfatin)的表达情况,探讨其在非酒精性脂肪性肝病(nonalcoholic fattyliver disease,NAFLD)发生、发展过程中的作用.以高脂饮食构建NAFLD大鼠模型,应用酶联免疫吸附法、RT-PCR及免疫组织化学等方法,动态检测大鼠NAFLD发展过程中血清Visfatin的含量及其在肝组织中的表达.结果显示:在模型组大鼠由单纯性脂肪肝(SS)发展为非酒精性脂肪性肝炎(NASH)的过程中,Visfatin在大鼠血清和肝组织中的表达均呈现由高到低的变化趋势,SS组大鼠Visfatin的表达显著高于正常对照组和NASH组(P<0.01),而正常对照组和NASH组之间无明显差异;SS组大鼠Visfatin主要表达于小叶中央静脉周围脂肪变性相对较轻的肝细胞内.由此认为,Visfatin在血清和肝组织中的高表达作为早期事件,可能在NAFLD发展过程中起重要作用.     

内脂素与2型糖尿病关系的研究进展

内脂素是新近被发现的主要由内脏脂肪合成的一种脂肪细胞因子,它具有类胰岛素样作用,能降低血糖和促进脂肪组织的分化与合成。内脂素还可以调节血管平滑肌的成熟和影响胰岛细胞的胰岛素的分泌,亦具有调节炎症反应和免疫功能的作用。随着研究的发展,人们对内脂素的结构特性、分布、表达调控及其生物学功能有了更加深入的认识。2型糖尿病是以胰岛素抵抗和糖代谢紊乱为特征的代谢性疾病,研究发现内脂素与2型糖尿病密切相关,其中与肥胖、胰岛素抵抗及胰岛素分泌方面的关系尤为显著,深入研究内脂素的生理和病理生理作用将会有力地促进对2型糖尿病的进一步认识、治疗与预防。     

Potential role of leptin, adiponectin and three novel adipokines--visfatin, chemerin and vaspin--in chronic hepatitis

Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Steatosis, independently of its metabolic or viral origin, leads to liver injury and fibrosis. It is suggested that hepatitis C virus may contribute to a wide spectrum of metabolic disturbances-namely, steatosis, insulin resistance, increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and lipid metabolism abnormalities. Adipokines, which are produced mainly by adipose tissue, may influence the inflammatory response and insulin sensitivity and contribute to the development of metabolic abnormalities in CHC and also regulate fibrogenesis and angiogenesis. Visfatin was described as an adipokine with immunomodulating and proinflammatory properties that promotes B-cell maturation and enhances activation of leukocytes, synthesis of adhesion molecules and production of proinflammatory cytokines. Visfatin exerts insulin-mimetic effects, decreases plasma glucose levels and regulates cell energy balance. Chemerin stimulates chemotaxis of dendritic cells, macrophages and natural killer (NK) cells toward the site of inflammation. On the other hand, it inhibits synthesis of proinflammatory mediators and enhances adiponectin production, influences adipocyte differentiation and maturation and regulates glucose uptake in adipocytes. Vaspin expression in human adipose tissue seems to be a compensatory mechanism associated with obesity and insulin resistance. Vaspin suppresses leptin, tumor necrosis factor (TNF)-α and resistin expression. Leptin protects against liver steatosis but accelerates fibrosis progression and exacerbates the inflammatory process. In contrast, adiponectin exerts a hepatoprotective effect. In this report, data indicating a possible role of these adipokines in the pathogenesis of chronic hepatitis are summarized.     

The metabolic syndrome and adipocytokines

Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases.     

Lack of direct insulin-like action of visfatin/Nampt/PBEF1 in human adipocytes

Visfatin, a protein identified as a secretion product of visceral fat in humans and mice, is also expressed in different anatomical locations, and is known as pre-B cell-colony enhancing factor (PEBF1). It is also an enzyme displaying nicotinamide phosphoribosyltransferase activity (Nampt). The evidence that levels of visfatin correlate with visceral fat mass has been largely debated and widely extended to other regulations in numerous clinical studies and in diverse animal models. On the opposite, the initial findings regarding the capacity of visfatin/Nampt/PEBF1 to bind and to activate the insulin receptor have been scarcely reproduced, and even were contradicted in recent reports. Since the putative insulin mimicking effects of visfatin/Nampt/PEBF1 have never been tested on mature human adipocytes, at least to our knowledge, we tested different human visfatin batches on human fat cells freshly isolated from subcutaneous abdominal fat and exhibiting high insulin responsiveness. Up to 10 nM, visfatin was devoid of clear activatory action on glucose transport in human fat cells while, in the same conditions, insulin increased by more than threefold the basal 2-deoxyglucose uptake. Moreover, visfatin was unable to mimic the lipolysis inhibition induced by insulin. Visfatin definitively cannot be considered as a direct activator of insulin signalling in human fat cells. Nevertheless its in vivo effects on insulin release and on glucose handling deserve to further study the role of this multifunctional extracellular enzyme in obese and diabetic states.     

Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells

Visfatin, which is secreted as an adipokine and cytokine, has been implicated in cancer development and progression. In this study, we investigated the NAD‐producing ability of visfatin and its relationship with SIRT1 (silent information regulator 2) and p53 to clarify the role of visfatin in breast cancer. MCF‐7 breast cancer cells were cultured and treated with visfatin. SIRT1 activity was assessed by measuring fluorescence intensity from fluoro‐substrate peptide. To investigate the effect of visfatin on p53 acetylation, SDS‐PAGE followed by western blotting was performed using specific antibodies against p53 and its acetylated form. Total NAD was measured both in cell lysate and the extracellular medium by colorimetric method. Visfatin increased both extracellular and intracellular NAD concentrations. It also induced proliferation of breast cancer cells, an effect that was abolished by inhibition of its enzymatic activity. Visfatin significantly increased SIRT1 activity, accompanied by induction of p53 deacetylation. In conclusion, the results show that extracellular visfatin produces NAD that causes upregulation of SIRT1 activity and p53 deacetylation. These findings explain the relationship between visfatin and breast cancer progression.     

Visfatin is released from 3T3-L1 adipocytes via a non-classical pathway

Visfatin is a secretory protein which exerts insulin mimetic and proinflammatory effects, also functioning as an intracellular enzyme to produce NAD. Plasma visfatin levels and visfatin mRNA expression in adipose tissues are increased in obese subjects. Visfatin does not have a decent cleavable signal sequence, and the mechanism, that mediates release of visfatin from adipocytes, remains poorly understood. In this study, we demonstrate that visfatin is released abundantly into culture medium from 3T3-L1 adipocytes. Subcellular fractionation analysis showed that visfatin was localized in the cytosol, but not in nucleus, membrane, vesicles, or mitochondria fractions. Visfatin release was not reduced by Brefeldin A and Monensin, inhibitors of endoplasmic reticulum (ER)-Golgi-dependent secretion. In addition, visfatin was not released on microvesicles. These results suggest that visfatin should be released from 3T3-L1 adipocytes via an ER-Golgi or microvesicles independent pathway.     

Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway

The biologically active factors known as adipocytokines are secreted primarily by adipose tissues and can act as modulators of angiogenesis. Visfatin, an adipocytokine that has recently been reported to have angiogenic properties, is upregulated in diabetes, cancer, and inflammatory diseases. Because maintenance of an angiogenic balance is critically important in the management of these diseases, understanding the molecular mechanism by which visfatin promotes angiogenesis is very important. In this report, we describe our findings demonstrating that visfatin stimulates the mammalian target of the rapamycin (mTOR) pathway, which plays important roles in angiogenesis. Visfatin induced the expression of hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) in human endothelial cells. Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of visfatin. The visfatin-induced increase in VEGF expression was also eliminated by RNA interference-mediated knockdown of the 70-kDa ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR. Visfatin inactivated glycogen synthase kinase 3β (GSK3β) by phosphorylating it at Ser-9, leading to the nuclear translocation of β-catenin. Both rapamycin co-treatment and p70S6K knockdown inhibited visfatin-induced GSK3β phosphorylation at Ser-9 and nuclear translocation of β-catenin. Taken together, these results indicate that mTOR signaling is involved in visfatin-induced angiogenesis, and that this signaling leads to visfatin-induced VEGF expression and nuclear translocation of β-catenin.     

Visfatin, an adipocytokine with proinflammatory and immunomodulating properties

Adipocytokines are mainly adipocyte-derived cytokines regulating metabolism and as such are key regulators of insulin resistance. Some adipocytokines such as adiponectin and leptin affect immune and inflammatory functions. Visfatin (pre-B cell colony-enhancing factor) has recently been identified as a new adipocytokine affecting insulin resistance by binding to the insulin receptor. In this study, we show that recombinant visfatin activates human leukocytes and induces cytokine production. In CD14(+) monocytes, visfatin induces the production of IL-1beta, TNF-alpha, and especially IL-6. Moreover, it increases the surface expression of costimulatory molecules CD54, CD40, and CD80. Visfatin-stimulated monocytes show augmented FITC-dextran uptake and an enhanced capacity to induce alloproliferative responses in human lymphocytes. Visfatin-induced effects involve p38 as well as MEK1 pathways as determined by inhibition with MAPK inhibitors and we observed activation of NF-kappaB. In vivo, visfatin induces circulating IL-6 in BALB/c mice. In patients with inflammatory bowel disease, plasma levels of visfatin are elevated and its mRNA expression is significantly increased in colonic tissue of Crohn's and ulcerative colitis patients compared with healthy controls. Macrophages, dendritic cells, and colonic epithelial cells might be additional sources of visfatin as determined by confocal microscopy. Visfatin can be considered a new proinflammatory adipocytokine.