脂肪细胞因子对代谢的调节

脂肪组织可将多余能量以甘油三酯(triglycerides,TG)形式储存,在饥饿状态下可分解TG产生游离脂肪酸(free fatty acids,FFAs)为机体供能。此外,脂肪组织还具有体温调节和器官保护功能,并且越来越多的证据表明,脂肪组织也是一种重要的内分泌组织。脂肪组织分泌的蛋白质物质被称为脂肪细胞因子(adipokine),可通过自分泌、旁分泌和内分泌方式发挥多种生物学功能,例如调节能量摄入和能量消耗,调节糖脂代谢,抗炎和促炎反应。对整体而言,脂肪细胞因子可调节大脑、肝、肌肉、血管系统、心、胰腺和免疫系统等不同靶器官的生物反应。其中,脂肪细胞因子在糖脂代谢中发挥特定的作用,包括:葡萄糖代谢[瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)];胰岛素敏感性 [瘦素、脂联素、锌-α2-糖蛋白(zinc-α2-glycoprotein,ZAG)];脂肪形成[骨形成蛋白4(bone morphogenetic protein 4,BMP4)]等生物反应过程。但目前对脂肪组织功能障碍与代谢之间机制的理解尚不完善。脂肪组织功能发生紊乱时,脂肪细胞因子的分泌会发生改变,并可能导致一系列与肥胖相关的代谢性疾病的发生。临床前和临床研究表明,激活或抑制特定脂肪细胞因子的信号转导可能是一种适合干预代谢疾病的方法。本文就部分脂肪细胞因子对代谢的调控作用做出综述,以增强对脂肪细胞因子功能的理解。     

Adipokines influence the inflammatory balance in autoimmunity

Over the past few decades, our understanding of the role of adipose tissue has changed dramatically. Far from simply being a site of energy storage or a modulator of the endocrine system, adipose tissue has emerged as an important regulator of multiple important processes including inflammation. Adipokines are a diverse family of soluble mediators with a range of specific actions on the immune response. Autoimmune diseases are perpetuated by chronic inflammatory responses but the exact etiology of these diseases remains elusive. While researchers continue to investigate these causes, millions of people continue to suffer from chronic diseases. To this end, an increased interest has developed in the connection between adipose tissue-secreted proteins that influence inflammation and the onset and perpetuation of autoimmunity. This review will focus on recent advances in adipokine research with specific attention on a subset of adipokines that have been associated with autoimmune diseases.     

Stimulation of PAI-1 and adipokines by glucose in human adipose tissue in vitro

Adipokines such as Plasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are elevated in patients with obesity, insulin resistance, and type 2 diabetes. In the present study, we investigated whether glucose affected the production of these adipokines in human adipose tissue in vitro. Glucose (up to 35mM) increased secretion of PAI-1 (p<0.01) and IL-8 (p<0.01), but not TNF-alpha, in a dose- and time-dependent manner. Half-maximal stimulatory concentration of glucose was about 1mM. Glucosamine (5mM) decreased production of PAI-1 (p<0.05) and IL-8 (p<0.05), indicating that the hexosamine biosynthesis pathway is not involved in the glucose-induced increment in adipokine secretion. The present data demonstrate that glucose increases PAI-1 and IL-8 secretion. However, glucose concentrations above 5mM had no additional effects on adipokine secretion, suggesting that mechanisms other than diabetes/insulin resistance-related hyperglycemia may be involved in the observed elevation of these adipokines.     

Adipokines oversecreted by omental adipose tissue in human obesity

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.     

Transport of nutrients and hormones through the blood-brain barrier

The transport of circulating nutrients (glucose, amino acids, ketone bodies, choline, and purines) through the brain endothelial wall, i.e., the blood-brain barrier (BBB), is an important regulatory step in several substrate-limited pathways of brain metabolism. The in vivo kinetics of nutrient transport has been well characterized in the rat, and the kinetic constants of saturable (Km, Vmax) and nonsaturable (KD) transport through the BBB are now known for more than 30 circulating nutrients. The kinetic constants can be used to gain insight into the important rate-limiting role played by BBB nutrient transport in the regulation of brain metabolism and function. Unlike most nutrients, steroid and thyroid hormones circulate tightly bound to plasma proteins. However, owing to favorable kinetic relationships among brain capillary transit times and rates of hormone dissociation from plasma proteins and hormone diffusion through the brain endothelia, the BBB is able to strip hormones off circulating plasma proteins. With regard to peptide hormone, no specific BBB transport systems for peptides have been identified thus far. However, peptides are able to rapidly distribute into brain interstitial space at the circumventricular organs. In addition, specific receptors for insulin are located on the BBB. The presence of BBB peptide receptors provides a mechanism by which circulating peptides may rapidly influence brain function without the peptide crossing the BBB.     

Seminal plasma adipokines: involvement in human reproductive functions

Infertility, which increased worldwide over the past few decades, has recently been linked to obesity prevalence. Adipokines, produced by adipose tissue, could be the link between obesity and infertility. The association between circulating adipokines and female infertility has been extensively studied in the last ten years. However, the male aspect has been less investigated, although some adipokines are present in seminal plasma. We have attempted to analyze published studies that measured seminal plasma adipokines and their relationships with semen parameters. Apart from leptin, other seminal adipokines have rarely been studied. Indeed, leptin seems to have a differential role depending on its concentration in the seminal plasma. Thus, it could have a beneficial effect at lower concentrations but a deleterious effect at higher seminal levels. Although some studies are currently available, the roles of leptin and other adipokines in seminal plasma on sperm parameters and their consequences on male fertility remain to be clarified.     

Specific AHNAK expression in brain endothelial cells with barrier properties

The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. Because disruption of the BBB may contribute to many brain disorders, they are of considerable interests in the identification of the molecular mechanisms of BBB development and integrity. We here report that the giant protein AHNAK is expressed at the plasma membrane of endothelial cells (ECs) forming specific blood-tissue barriers, but is absent from the endothelium of capillaries characterized by extensive molecular exchanges between blood and extracellular fluid. In the brain, AHNAK is widely distributed in ECs with BBB properties, where it co-localizes with the tight junction protein ZO-1. AHNAK is absent from the permeable brain ECs of the choroid plexus and is down-regulated in permeable angiogenic ECs of brain tumors. In the choroid plexus, AHNAK accumulates at the tight junctions of the choroid epithelial cells that form the blood-cerebrospinal fluid (CSF) barrier. In EC cultures, the regulation of AHNAK expression and its localization corresponds to general criteria of a protein involved in barrier organization. AHNAK is up-regulated by angiopoietin-1 (Ang-1), a morphogenic factor that regulates brain EC permeability. In bovine cerebral ECs co-cultured with glial cells, AHNAK relocates from the cytosol to the plasma membrane when endothelial cells acquire BBB properties. Our results identify AHNAK as a protein marker of endothelial cells with barrier properties.     

Microbial translocation of the blood-brain barrier

A major contributing factor to high mortality and morbidity associated with CNS infection is the incomplete understanding of the pathogenesis of this disease. Relatively small numbers of pathogens account for most cases of CNS infections in humans, but it is unclear how such pathogens cross the blood-brain barrier (BBB) and cause infections. The development of the in vitro BBB model using human brain microvascular endothelial cells has facilitated our understanding of the microbial translocation of the BBB, a key step for the acquisition of CNS infections. Recent studies have revealed that microbial translocation of the BBB involves host cell actin cytoskeletal rearrangements, most likely as the result of specific microbial-host interactions. A better understanding of microbial-host interactions that are involved in microbial translocation of the BBB should help in developing new strategies to prevent CNS infections. This review summarises our current understanding of the pathogenic mechanisms involved in translocation of the BBB by meningitis-causing bacteria, fungi and parasites.     

Modulation of feeding-related peptide/protein signals by the blood-brain barrier

The peptide urocortin is a member of the corticotropin-releasing factor (CRF) family and a potent satiety signal to the brain. Urocortin in blood does not reach the brain significantly by itself, but its permeation across the blood-brain barrier (BBB) can be enhanced by leptin. How leptin facilitates the influx of urocortin has not been elucidated. In this study, we tested the hypothesis that leptin activates receptor-mediated endocytosis of urocortin. We measured the kinetics of permeation of radioactively labeled urocortin across the mouse BBB and determined the specific effects of leptin and receptor antibodies. The results show that the influx transfer constant of urocortin was enhanced in the presence of leptin and mediated by CRF-2beta, the specific receptor for urocortin. To determine the specificity of this modulation, the effect of leptin was compared with that of TNFalpha. Both TNFalpha and leptin independently facilitated receptor-mediated transport of urocortin across the BBB. Even though TNFalpha and leptin have similar effects on urocortin transport, leptin did not significantly affect the influx of TNFalpha across the BBB. The results indicate that permeation of ingestive peptides and cytokines across the BBB can be acutely modulated, consistent with a role of BBB in regulating feeding behavior. Thus, sites of action of leptin, urocortin, and TNFalpha exist not only in the brain but also at the BBB where they each control the flow of other ingestive signals to CNS targets.     

Leptin to adiponectin ratio as a useful predictor for cardiac syndrome X

Objective: The role of adipokines in the development of cardiac syndrome X (CSX) remains unknown.

Methods: Fifty-nine CSX subjects were retrospectively enrolled from our catheterization databank. Another 54 subjects with valvular heart disease or arrhythmia served as controls. Adipokines were measured by ELISA tests.

Results: The CSX had lower circulating adiponectin but higher leptin and higher leptin/adiponectin ratio (×1000) (3.78?±?4.96 vs. 2.14?±?5.67, p < 0.001) than those of the controls. In a multivariate analysis, a higher leptin/adiponectin ratio was a predictor of CSX, while insulin-resistance index was not.

Conclusions: Adipokines may be implicated in the pathogenesis of CSX.     

Divergent effects of zinc depletion in brain vs non-brain endothelial cells

Dietary zinc deficiency is common in developing as well as developed countries. Endothelial cells (EC) lining the inner surface of peripheral blood vessels are sensitive to zinc deficiency and lose structural integrity when exposed to culture media low in zinc or to zinc chelators. In contrast, we demonstrate here that human brain microvascular EC (HBMEC), which constitute the blood-brain barrier (BBB), resist zinc depletion and respond by enhancing their barrier function. This response was specific for HBMEC and did not occur in non-brain EC, such as human umbilical vein endothelial cells, human aortic endothelial cells, and human iliac vein endothelial cells. Our results suggest the presence of specific mechanisms to counteract zinc deficiency at the BBB, likely involving HBMEC junctional complexes. Understanding the mechanisms involved in this unique response might provide means to modulate the BBB dysfunction associated with neurological disorders such as stroke, multiple sclerosis, and Alzheimer's disease.     

Do novel adipokines play a causative or only modulating role in the pathogenesis of obesity and metabolic disorders?

Adipose tissue is an endocrine and paracrine organ that releases a large number of bioactive mediators. Approximately 100 adipokines have been identified including cytokines, chemokines, growth factors and enzymes. The use of adipoproteomic analyses resulted in new findings and, in consequence, the number of new adipokines is rising rapidly. Novel adipokines such as visfatin, vaspin and omentin were discovered about five years ago. Visfatin and vaspin production and secretion take place in adipocytes, but omentin comes from the stromal cells of adipose tissue. Several differences are noticeable between these adipokines especially in correlation with obesity as visfatin and vaspin serum levels increase in obese subjects while omentin serum levels decrease. It has been suggested that these adipokines act as insulin-sensitizers/insulin-mimetics. Increasing number of publications reporting the role of new adipokines does not allow to assess clearly the influence of those adipokines on the pathogenesis of obesity.     

Protection of the blood-brain barrier during acute and chronic hypertension

A new concept about sympathetic nerves has emerged recently: not only is sympathetic tone important in short-term regulation of vascular resistance, but chronic effects of nerves on vessels have important effects. This concept is supported by studies of mechanisms by which sympathetic nerves protect the blood-brain barrier (BBB). The BBB is susceptible to disruption during acute and chronic hypertension. Acute, severe hypertension produces passive dilatation of cerebral vessels with disruption of the BBB. Sympathetic stimulation attenuates the increase in cerebral blood flow during acute hypertension and thereby protects the BBB. During chronic hypertension, we have observed disruption of the barrier, which may contribute to hypertensive encephalopathy. Sympathetic nerves protect against disruption of the BBB during chronic hypertension. This protective effect is apparently related to a trophic effect of nerves in promotion of cerebral vascular hypertrophy during chronic hypertension. Thus, this is the first evidence that, in the same vascular bed, sympathetic nerves have two different protective effects. Protection of the BBB is accomplished acutely by sympathetic neural effects on vascular resistance and chronically by promotion of vascular hypertrophy.     

脂肪细胞对胰岛β细胞功能的内分泌调节作用

脂肪因子包括脂肪细胞分泌的多种活性因子,它们通过内分泌方式调节胰岛β细胞的胰岛素分泌、基因表达以及细胞凋亡等多方面的功能。本文提出脂肪因子影响胰岛β细胞功能主要通过三条相互联系的途径而实现。第一是调节β细胞内葡萄糖和脂肪的代谢;第二是影响β细胞离子通道的活性;第三是改变β细胞本身的胰岛素敏感性。脂肪细胞的内分泌功能是一个动态过程,在不同的代谢状态下,各脂肪因子的分泌发生不同变化。从正常代谢状态发展到肥胖以及2型糖尿病的过程中,脂肪因子参与了胰岛β细胞功能障碍的发生与发展。     

Effects of oxysterols on the blood–brain barrier: Implications for Alzheimer’s disease

Altered brain cholesterol homeostasis plays a key role in neurodegenerative diseases such as Alzheimer’s disease (AD). For a long time, the blood–brain barrier (BBB) was basically considered as a barrier isolating the brain from circulating cholesterol, however, several lines of evidence now suggest that the BBB strictly regulates the exchanges of sterol between the brain and the peripheral circulation. Oxysterols, synthesized by neurons or by peripheral cells, cross the BBB easily and modulate the expression of several enzymes, receptors and transporters which are involved not only in cholesterol metabolism but also in other brain functions. This review article deals with the way oxysterols impact BBB cells. These perspectives open new routes for designing certain therapeutical approaches that target the BBB so that the onset and/or progression of brain diseases such as AD may be modulated.     

Pericytes from Brain Microvessels Strengthen the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells

(1) The blood–brain barrier (BBB) characteristics of cerebral endothelial cells are induced by organ-specific local signals. Brain endothelial cells lose their phenotype in cultures without cross-talk with neighboring cells. (2) In contrast to astrocytes, pericytes, another neighboring cell of endothelial cells in brain capillaries, are rarely used in BBB co-culture systems. (3) Seven different types of BBB models, mono-culture, double and triple co-cultures, were constructed from primary rat brain endothelial cells, astrocytes and pericytes on culture inserts. The barrier integrity of the models were compared by measurement of transendothelial electrical resistance and permeability for the small molecular weight marker fluorescein. (4) We could confirm that brain endothelial monolayers in mono-culture do not form tight barrier. Pericytes induced higher electrical resistance and lower permeability for fluorescein than type I astrocytes in co-culture conditions. In triple co-culture models the tightest barrier was observed when endothelial cells and pericytes were positioned on the two sides of the porous filter membrane of the inserts and astrocytes at the bottom of the culture dish. (5) For the first time a rat primary culture based syngeneic triple co-culture BBB model has been constructed using brain pericytes beside brain endothelial cells and astrocytes. This model, mimicking closely the anatomical position of the cells at the BBB in vivo, was superior to the other BBB models tested. (6) The influence of pericytes on the BBB properties of brain endothelial cells may be as important as that of astrocytes and could be exploited in the construction of better BBB models.     

Ischemia-induced stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransport involves p38 and JNK MAP kinases

Previous studies have provided evidence that, in the early hours of ischemic stroke, a luminal membrane blood-brain barrier (BBB) Na-K-Cl cotransporter (NKCC) participates in ischemia-induced cerebral edema formation. Inhibition of BBB NKCC activity by intravenous bumetanide significantly reduces edema and infarct in the rat permanent middle cerebral artery occlusion model of ischemic stroke. We demonstrated previously that the BBB cotransporter is stimulated by hypoxia, aglycemia, and AVP, factors present during cerebral ischemia. However, the underlying mechanisms have not been known. Ischemic conditions have been shown to activate p38 and JNK MAP kinases (MAPKs) in brain, and the p38 and JNK inhibitors SB-239063 and SP-600125, respectively, have been found to reduce brain damage following middle cerebral artery occlusion and subarachnoid hemorrhage, respectively. The present study was conducted to determine whether one or both of these MAPKs participates in ischemic factor stimulation of BBB NKCC activity. Cultured cerebral microvascular endothelial cell NKCC activity was evaluated as bumetanide-sensitive (86)Rb influx. Activities of p38 and JNK were assessed by Western blot and immunofluorescence methods using antibodies that detect total vs. phosphorylated (activated) p38 or JNK. We report that p38 and JNK are present in cultured cerebral microvascular endothelial cells and in BBB endothelial cells in situ and that hypoxia (7% O(2) and 2% O(2)), aglycemia, AVP, and O(2)-glucose deprivation (5- to 120-min exposures) all rapidly activate p38 and JNK in the cells. We also provide evidence that SB-239063 and SP-600125 reduce or abolish ischemic factor stimulation of BBB NKCC activity. These findings support the hypothesis that ischemic factor stimulation of the BBB NKCC involves activation of p38 and JNK MAPKs.     

Novel insights into the development and maintenance of the blood–brain barrier

The blood–brain barrier (BBB) is essential for maintaining homeostasis within the central nervous system (CNS) and is a prerequisite for proper neuronal function. The BBB is localized to microvascular endothelial cells that strictly control the passage of metabolites into and out of the CNS. Complex and continuous tight junctions and lack of fenestrae combined with low pinocytotic activity make the BBB endothelium a tight barrier for water soluble moleucles. In combination with its expression of specific enzymes and transport molecules, the BBB endothelium is unique and distinguishable from all other endothelial cells in the body. During embryonic development, the CNS is vascularized by angiogenic sprouting from vascular networks originating outside of the CNS in a precise spatio-temporal manner. The particular barrier characteristics of BBB endothelial cells are induced during CNS angiogenesis by cross-talk with cellular and acellular elements within the developing CNS. In this review, we summarize the currently known cellular and molecular mechanisms mediating brain angiogenesis and introduce more recently discovered CNS-specific pathways (Wnt/β?catenin, Norrin/Frizzled4 and hedgehog) and molecules (GPR124) that are crucial in BBB differentiation and maturation. Finally, based on observations that BBB dysfunction is associated with many human diseases such as multiple sclerosis, stroke and brain tumors, we discuss recent insights into the molecular mechanisms involved in maintaining barrier characteristics in the mature BBB endothelium.     

Glycolysis-mediated control of blood-brain barrier development and function

The blood-brain barrier (BBB) consists of differentiated cells integrating in one ensemble to control transport processes between the central nervous system (CNS) and peripheral blood. Molecular organization of BBB affects the extracellular content and cell metabolism in the CNS. Developmental aspects of BBB attract much attention in recent years, and barriergenesis is currently recognized as a very important and complex mechanism of CNS development and maturation. Metabolic control of angiogenesis/barriergenesis may be provided by glucose utilization within the neurovascular unit (NVU). The role of glycolysis in the brain has been reconsidered recently, and it is recognized now not only as a process active in hypoxic conditions, but also as a mechanism affecting signal transduction, synaptic activity, and brain development. There is growing evidence that glycolysis-derived metabolites, particularly, lactate, affect barriergenesis and functioning of BBB. In the brain, lactate produced in astrocytes or endothelial cells can be transported to the extracellular space via monocarboxylate transporters (MCTs), and may act on the adjoining cells via specific lactate receptors. Astrocytes are one of the major sources of lactate production in the brain and significantly contribute to the regulation of BBB development and functioning. Active glycolysis in astrocytes is required for effective support of neuronal activity and angiogenesis, while endothelial cells regulate bioavailability of lactate for brain cells adjusting its bidirectional transport through the BBB. In this article, we review the current knowledge with regard to energy production in endothelial and astroglial cells within the NVU. In addition, we describe lactate-driven mechanisms and action of alternative products of glucose metabolism affecting BBB structural and functional integrity in developing and mature brain.     

Holey barrier: claudins and the regulation of brain endothelial permeability

Endothelial tight junctions (TJs)* are an important functional part of the blood-brain barrier (BBB). In this issue, Nitta et al. (2003) demonstrate that claudin-5, a transmembrane protein of TJs, is a critical determinant of BBB permeability in mice. Unexpectedly, knockout of claudin-5 did not result in a general breakdown of TJs but in a selective increase in paracellular permeability of small molecules. This suggests that the BBB can be manipulated to allow selective diffusion of small molecules and makes claudin-5 a possible target for the development of drugs for this purpose.