脂肪因子对血管内皮细胞功能的影响

肥胖患者缺血性心血管疾病的发病危险性显著升高虽已是不争的事实,但脂肪组织与缺血性心血管疾病基本病理变化--动脉粥样硬化之间病理生理联系却至今仍未清楚阐明.近年来国内外大量研究结果表明,脂肪组织亦是重要的内分泌器官,脂肪组织可分泌释放多种具有生物活性的蛋白质分子(脂肪因子)进入血循环,如瘦素、脂联素等,脂肪组织通过这些脂肪因子调节机体的内分泌代谢等功能,从而在维持机体能量平衡方面发挥着举足轻重的作用.而更令人兴奋的发现是这些脂肪因子对血管的功能及结构也有重要的调节作用.围绕这一领域所进行的研究正逐步展示出脂肪一血管轴功能异常在代谢综合征缺血性心血管疾病中的重要作用.本文结合国内外近几年来在脂肪因子与血管内皮细胞功能之间关系的研究进展作一简要综述.     

脂肪组织功能紊乱与胰岛素抵抗

脂肪组织且前被视为一个高度活跃的代谢和内分泌器官。脂肪细胞可以通过自身聚脂对日常膳食的脂肪起缓冲作用．还能分泌各种脂肪因子而调节全身或局部的能量代谢。脂肪组织的功能紊乱时．机体可出现肥胖．并且有越来越多的证据表明．脂肪组织的功能障碍在胰岛素抵抗（insulin resistance．IR）的发生和进展中起着主要作用。     

内脂素与肥胖相关性疾病的研究

脂肪组织不仅能调节能量储存与营养平衡,而且还是活跃的内分泌器官,可分泌多种脂肪细胞因子,如瘦素、抵抗素、脂联索、网膜素等,这些脂肪因子具有广泛的内分泌及心血管活性作用.肥胖时随着脂肪的堆积以及脂肪细胞体积的增大,脂肪因子分泌失调,可引起多种代谢紊乱,如高脂血症、胰岛素抵抗、糖尿病、代谢综合征等.内脂素(visfatin)是新近发现的主要由内脏脂肪组织分泌的一种脂肪细胞因子,具有类胰岛素活性,降低血糖、调节糖脂代谢、参与炎性反应及免疫应答等多种生物学功能.现有研究表明,vifatin可能与冠心病、高血压、糖尿病等一系列肥胖相关性疾病密切相关.本文简述visfatin生物学效应及其在肥胖及肥胖相关性疾病中的研究进展.     

网膜素与胰岛素抵抗的关系

脂肪组织主要由嵌人在疏松结缔组织中的脂肪细胞组成,内含脂肪细胞前体成纤维细胞、免疫细胞和其他类型的细胞。近年来研究表明,脂肪组织不仅是传统的能量储存器官,还是一个功能活跃的内分泌器官,分泌多种脂肪细胞因子,如网膜素、脂联素、肿瘤坏死因子（TNF-a）、瘦素、抵抗素、白细胞介素（IL）-6等,这些脂肪细胞因子通过多种途径来影响胰岛素的生物学效应,参与胰岛素抵抗（IR）及其相关疾病,如肥胖、2型糖尿病及代谢综合征的发生、发展。     

脂肪内分泌学研究进展

长期以来,人们传统地认为脂肪组织仅仅是一个被动储存能量和释放能量的器官,然而,过去10年的精彩研究打破了这种传统的看法,特别是1994年瘦素(Leptin)的发现,Zhang等更新了人们对脂肪组织是一个内分泌器官的认识,并激发了人们对脂肪内分泌功能的极大兴趣.现在认为,脂肪组织是一个高度活跃的内分泌器官,它分泌许多脂肪细胞因子和蛋白质因子,发挥局部(自分泌、旁分泌)和远处(内分泌)的作用.脂肪细胞通过其所分泌的诸多信号分子在调节机体代谢、生殖、心血管功能和免疫方面发挥重要作用,下面就近年的一些相对完善的研究资料对脂肪组织内分泌功能作一简单综述.     

缺氧对脂肪细胞内分泌功能的影响

脂肪组织是一个活跃的代谢和内分泌器官,分泌许多细胞因子和生物活性因子,参与能量代谢及平衡、介导炎症应答等。研究发现,肥胖个体脂肪组织存在局部缺氧[1],并且缺氧可使炎症因子表达失调[2],这为肥胖发病机制的研究提供了新的方向和思路。本文就脂肪细胞分泌的相关炎症因子做一简要综述。     

视黄醇结合蛋白4与心血管疾病的研究

<正>人体脂肪组织不但具有储存能量的功能,而且还是一个重要的内分泌器官,它可以分泌大量的脂肪细胞因子,如网膜素、脂联素、视黄醇结合蛋白(RBP)等,还可以分泌许多生物活性物质。其中RBP-4是较新发现的一种脂肪细胞因子,有研究表明它在脂肪代谢和能量平衡中起重要作用。当前研究认为脂肪组织所分泌的脂肪细胞因子在肥胖、心血管疾病、代谢综合征及2型糖尿病等疾病中发挥着重要作用。本文对RBP-4在心血管疾病中所起     

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。     

肥胖相关高血压的体液调节机制的新进展

肥胖是发生高血压的独立危险因素。现已证实肥胖相关的高血压的发病和维持是通过体液调节机制实现的,激素、细胞因子、生物活性肽等通过循环激素、自分泌、旁分泌及细胞内分泌的方式调节着代谢、食欲和血压。脂肪分泌的多种体液因子瘦素、脂联素、抵抗素、脂肪RAS等,以及其它体液因子ghrelin,肽YY,增食因子等,在肥胖相关的高血压的发病过程中起着重要作用。深入研究它们在食欲和代谢方面的调节机制,可为肥胖相关高血压的治疗提供新靶点。     

把胖相关高血压的体液调节机制的新进展

肥胖是发生高血压的独立危险因素。现已证实肥胖相关的高血压的发病和维持是通过体液调节机制实现的,激素、细胞因子、生物活性肽等通过循环激素、自分泌、旁分泌及细胞内分泌的方式调节着代谢、食欲和血压。脂肪分泌的多种体液因子瘦素、脂联素、抵抗素、脂肪RAS等,以及其它体液因子ghrelin,肽YY,增食因子等,在肥胖相关的高血压的发病过程中起着重要作用。深入研究它们在食欲和代谢方面的调节机制,可为肥胖相关高血压的治疗提供新靶点。     

西格列汀对肥胖大鼠代谢指标及脂肪因子chemerin脂联素水平的影响

目的 研究西格列汀对肥胖大鼠代谢指标及脂肪因子chemerin、脂联素(ADPN)水平的影响及其可能机制,并探讨chemerin及ADPN与肥胖的关系。方法 将30只大鼠随机分为正常对照组(NC组)、肥胖对照组(HF组)和肥胖西格列汀干预组(SP组),ELISA法分别测定干预前后各组大鼠生化指标,Western blot 法检测大鼠脂肪、肝脏、肌肉及肾脏组织chemerin及ADPN蛋白表达水平。结果 与NC组相比,HF组大鼠血清chemerin、体质量(BW),空腹血糖(FBG)、胰岛素(FINS)、总胆固醇(TG)、甘油三酯(TC)、低密度脂蛋白胆固醇(LDL-C),胰岛素抵抗指数(HOMO-IR)增高,血清ADPN及高密度脂蛋白胆固醇(HDL-C)降低(P<0.05),HF组大鼠脂肪、肝脏、肌肉及肾脏组织的chemerin蛋白表达量较NC组对应组织的表达量增加(P<0.05),脂肪、肝脏及肌肉组织的ADPN表达量减少(P<0.05)。与HF组相比,SP组大鼠FBG、FINS、TC、TG、LDL-C、HOMO-IR、血清chemerin水平降低, HDL-C及血清ADPN水平升高(P<0.05),脂肪、肝脏、肾脏及肌肉组织的chemerin蛋白表达量减少,脂肪、肌肉组织的ADPN表达增加(P<0.05)。干预前chemerin、ADPN与BW、FBG、TG、HDL-C、LDL-C、FINS、HOMO-IR有相关性,干预后chemerin、ADPN与BW、LDL-C、FINS、HOMO-IR有相关性,ADPN与HDL-C呈正相关。结论 chemerin及ADPN参与糖脂代谢过程,西格列汀可改善血清学各代谢指标,并通过影响chemerin及ADPN来改善肥胖大鼠胰岛素敏感性。     

Chemerin/ChemR23 signaling axis is involved in the endothelial protection by K(ATP) channel opener iptakalim

Aim:

To elucidate the modulation of the chemerin/ChemR23 axis by iptakalim-induced opening of K_ATP channels and to determine the role of the chemerin/ChemR23 axis in the iptakalim-mediated endothelial protection.

Methods:

Cultured rat aortic endothelial cells (RAECs) were used. Chemerin secretion and ChemR23 protein expression were investigated using Western blot analysis. The gene expression level of ChemR23 was examined with RT-PCR. In addition, the release of nitric oxide (NO) was measured with a nitric oxide assay.

Results:

Homocysteine, uric acid, high glucose, or oxidized low-density lipoprotein (ox-LDL) down-regulated the chemerin secretion and ChemR23 gene/protein expression in RAECs as a function of concentration and time, which was reversed by pretreatment with iptakalim (1-10 μmol/L). Moreover, these effects of iptakalim were abolished in the presence of the K_ATP channel antagonist glibenclamide (1 μmol/L). Both iptakalim and recombinant chemerin restored the impaired NO production in RAECs induced by uric acid, and the effects were abolished by anti-ChemR23 antibodies.

Conclusion:

Iptakalim via opening K_ATP channels enhanced the endothelial chemerin/ChemR23 axis and NO production, thus improving endothelial function.     

Chemerin-induced arterial contraction is Gi- and calcium-dependent

Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S¹⁵⁷ isoform) caused a concentration-dependent contraction of isolated aorta (EC₅₀ 100 nM) and elicited a concentration-dependent intracellular calcium response (EC₅₀ 10 nM). Pertussis toxin (G_i inhibitor), verapamil (L-type Ca^2 + channel inhibitor), PP1 (Src inhibitor), and Y27632 (Rho kinase inhibitor) reduced both calcium influx and isometric contraction to chemerin-9 but PD098059 (Erk MAPK inhibitor) and U73122 (PLC inhibitor) had little to no effect on either measure of chemerin signaling. Although our primary aim was to examine chemerin signaling, we also highlight differences in the mechanisms of chemerin-9 and recombinant chemerin S¹⁵⁷. These data support a chemerin-induced contractile mechanism in vascular smooth muscle that functions through G_i proteins to activate L-type Ca^2 + channels, Src, and Rho kinase. There is mounting evidence linking chemerin to hypertension and this mechanism brings us closer to targeting chemerin as a form of therapy.     

Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1-deficient mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide implicated in several metabolic functions, including insulin secretion and sympathoadrenal activation. To clarify the roles of PACAP in maintenance of whole-body glucose and lipid homeostasis, the impact of the deletion of PACAP on glucose homeostasis, body weight, and adipose tissue mass was examined by comparing mice lacking the Adcyap1 gene encoding PACAP (Adcyap1(-/-)) with wild-type littermate controls. Adcyap1(-/-) mice showed significant hypoinsulinemia, although being normoglycemic, and lower body weight as well as reduced food intake. They also showed greatly reduced white adipose tissue mass, in which the mRNA expression of adipocyte fatty acid-binding protein (aP2), a marker of adipocyte differentiation, was decreased. Glucose and insulin tolerance tests revealed increased insulin sensitivity in Adcyap1(-/-) mice. In accordance with these observations, plasma levels of resistin, an adipocytokine implicated in insulin resistance, were decreased in Adcyap1(-/-) mice. After a high-fat dietary challenge for six weeks, Adcyap1(-/-) mice still showed lower body weights and increased insulin sensitivity. These results indicate the crucial roles of PACAP in energy metabolism, including lipid metabolism, and in the regulation of body weight, raising the possibility that the PACAP-signaling pathway that favors energy storage could be a therapeutic target for obesity.     

Chemerin in renal dysfunction and cardiovascular disease

The potential involvement of chemerin in cardiovascular and renal dysfunction has recently been acknowledged. There are indeed many links between this protein and inflammation, atherosclerosis, and multiple obesity- and diabetes-related parameters such as body mass index, insulin resistance, and blood levels of insulin, cholesterol, triglycerides, and glucose. In addition, in the last few years, several reports have investigated the circulating chemerin levels and their pathophysiologic significance in chronic kidney disease populations. However, there are still gaps in our understanding of this matter, in particular as to whether elevated chemerin might be the cause behind, or simply mirror, a reduced renal function.The limitations of the present knowledge on chemerin may partly relate to the lack of specific antibodies for assessing the different active isoforms of the protein. Measuring its bioactive serum concentration, and achieving a precise overall pattern of the tissue-specific formation of different isoforms, with the use of suitable technology, will ultimately help define the role of chemerin in disease pathophysiology, or as a diagnostic or therapeutic marker.     

Characterization of semicarbazide-sensitive amine oxidase in human subcutaneous adipocytes and search for novel functions

Numerous studies have characterized semicarbazide-sensitive amine oxidase activity (SSAO) in rat fat cells but this oxidase is scarcely documented in human adipose tissue. Our aim was to further characterize SSAO in human adipose tissue (activity, mRNA and protein abundance) and to investigate whether SSAO activity can interplay with glucose and lipid metabolism in human adipocytes via the hydrogen peroxide it generates. Polyclonal antibodies directed against bovine lung SSAO allowed the detection of a substantial amount of immunoreactive protein (apparent molecular mass 100 kDa) in human subcutaneous adipocytes from either mammary or abdominal fat depots. A 4-kb mRNA was detected in fat depots using a cDNA probe designed from the placenta SSAO sequence. Almost all the oxidation of benzylamine found in adipose tissue homogenates was due to fat cells and was located in the adipocyte membrane fraction. The oxidation of benzylamine and methylamine were similar and totally inhibited by semicarbazide or hydralazine but resistant to pargyline. Histamine was poorly oxidized. Benzylamine and methylamine dose-dependently stimulated glucose transport in intact adipocytes. This insulin-like effect of amines did not increase in the presence of 0.1 mM vanadate but was inhibited by semicarbazide and antioxidants. Benzylamine and methylamine also exhibited antilipolytic effects, with complete inhibition of lipolysis at 1 mM. These results show that fat cells from non-obese subjects express a membrane-bound SSAO which readily oxidizes exogenous amines, generates hydrogen peroxide and exerts short-term insulin-like actions on glucose and lipid metabolism.     

The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes

Adipocyte cell proliferation is an important process in body fat mass development in obesity. Adiponectin or Acrp30 is an adipocytokine exclusively expressed and secreted by adipose tissue that regulates lipid and glucose metabolism and plays a key role in body weight regulation and homeostasis. Adiponectin mRNA expression in adipose tissue and plasma level of adiponectin are decreased in obesity and type 2 diabetes. In obese rodents, the selective CB(1) receptor antagonist rimonabant reduces food intake and body weight and improves lipid and glucose parameters. We have reported previously that rimonabant stimulated adiponectin mRNA expression in adipose tissue of obese fa/fa rats, by a direct effect on adipocytes. We report here that rimonabant (10-400 nM) inhibits cell proliferation of cultured mouse 3T3 F442A preadipocytes in a concentration-dependent manner. In parallel to this inhibitory effect on preadipocyte cell proliferation, rimonabant (25-100 nM) stimulates mRNA expression and protein levels of two late markers of adipocyte differentiation (adiponectin and glyceraldehyde-3-phosphate dehydrogenase) with a maximal effect at 100 nM, without inducing the accumulation of lipid droplets. Furthermore, treatment of mouse 3T3 F442A preadipocytes with rimonabant (100 nM) inhibits basal and serum-induced p42/44 mitogen-activated protein (MAP) kinase activity. These results suggest that inhibition of MAP kinase activity by rimonabant may be one of mechanisms involved in the inhibition of 3T3 F442A preadipocyte cell proliferation and stimulation of adiponectin and GAPDH expression. The inhibition of preadipocyte cell proliferation and the induction of adipocyte late "maturation" may participate in rimonabant-induced antiobesity effects, particularly the reduction of body fat mass.