乳腺癌患者血清瘦素及可溶性瘦素受体的作用分析

目的：分析瘦素（leptin,Lp）及可溶性瘦素受体（soluble leptin receptor,sLR）水平在乳腺癌患者血清中的变化。方法：用放射免疫分析测定68例乳腺癌患者血清瘦素水平,并同步测量体重指数（MBI）和用酶联免疫吸附试验法检测可溶性瘦素受体水平,与31例良性乳腺疾病和40例健康体检者进行对照比较。结果：乳腺癌组血清瘦素水平显著高于健康对照组（P〈0．01）,消除体重指数的影响后,这种显著性差异依然存在;可溶性瘦素受体水平与对照组比水平下降（P〈0．05）,消除体重指数的影响后,这种显著性差异消失（P〉0．05）;良性乳腺疾病对照和健康对照之间均无显著性差异。结论：乳腺癌患者瘦素呈现过表达现象,瘦素与瘦素受体结合,促进肿瘤生长,瘦素可作为乳腺癌的潜在检测指标,其对于研究乳腺癌的发生发展、与肥胖的关系、辅助诊断乳腺癌都具有重要意义。     

瘦素的免疫调节作用及信号转导研究进展

瘦素(leptin)是一种主要调节能量代谢的蛋白类激素。瘦素可以促进多种免疫细胞的增殖、活化及细胞因子合成,促使免疫反应向Th1方向漂移,促进NK细胞的细胞毒作用,促进炎症反应,因此,瘦素在免疫系统中发挥着重要的调节作用。瘦素受体(leptin receptor,LEP-R)与其配体结合后主要通过JAK-STAT3通路来向胞内转导活化信号,调节转录。文章就瘦素对免疫组织器官、免疫细胞的生物学作用及其信号转导通路的研究进展作如下综述。     

瘦素及其受体的研究进展

瘦素在机体脂肪含量的调节中起着重要的作用。其生理作用是通过瘦素受体介导的。脂肪细胞合成、分泌瘦素 ,反过来瘦素作用于下丘脑维持着体脂的稳定性 ,高水平时通过促黑皮质素受体系统抑制摄食 ,低水平时通过神经肽Y促进摄食。瘦素和胰岛素有抑制人和动物摄食及降低体重的作用。肥胖患者存在瘦素抵抗。本文主要内容包括 :瘦素的生物学特性和生物学效应 ;瘦素受体的生物学特性及功能 ;瘦素的作用机制 ;瘦素、胰岛素与摄食量 ;瘦素抵抗与肥胖     

瘦素抵抗的研究进展

肥胖已成为现代社会中最常见的营养障碍性疾病 ,但其发病机制目前仍不清楚。在人类肥胖中瘦素基因突变和瘦素受体基因突变发生的机率都很少。肥胖者普遍存在着高瘦素血症 ,因此目前的研究热点集中在与肥胖有关的瘦素抵抗现象。本文从瘦素受体的信号转导途径、瘦素进入下丘脑的转运系统、可溶性瘦素受体和瘦素受体的下调现象等几个与瘦素抵抗相关问题对近年有关文献作一简要综述     

瘦素抵抗的免疫调节作用及其与肿瘤发生的关系

瘦素是一种内分泌激素,与受体结合后发挥调节食欲、能量代谢、生殖和造血等多种生物学作用.瘦素抵抗与肿瘤发生发展密切相关,除对肿瘤细胞的增殖及凋亡等发挥作用外,还参与调节肿瘤局部微环境中多种免疫细胞的数目与功能,通过调控抗肿瘤免疫活性参与肿瘤发生发展.目前已发现瘦素抵抗的免疫调节作用在多种类型肿瘤中发挥功能,对肿瘤的诊断与防治具有重要意义.     

瘦素受体基因研究进展

瘦素受体（leptin receptor,lepr)是瘦素调节机体能量代谢和脂肪沉积的重要中介物质,在机体内广泛分布,有多种拼接异构体型。动物试验发现其基因突变与肥胖、胰岛素抵抗及糖尿病相关。关于人体瘦素受体相关基因的研究虽起步较晚。但进展较快。     

肥胖与瘦素

肥胖的病因和发病机制尚未完全明了.其病因相当复杂,主要有环境因素和遗传因素.而近7年来对瘦素在调节体脂方面作用的研究,为认识肥胖提供更多的依据.本文对瘦素、瘦素受体以及瘦素的节律性分泌与肥胖的关系进行简要的综述,同时对运用瘦素治疗肥胖的意义前景做了展望.     

瘦素的信号转导机制

瘦素是由肥胖基因编码的一种多肽激素 ,具有调节能量代谢和抑制食欲的作用 ,其调节作用由瘦素受体所介导。瘦素受体属于 I类细胞因子受体家族。 JAK- STAT途径是瘦素信号转导的主要途径。瘦素与胰岛素的信号转导通路之间存在“cross talk”。     

瘦素系统对Th17细胞分化和功能的影响

Th17细胞在介导炎性反应、自身免疫性疾病、移植排斥和肿瘤等的发生发展中发挥着重要的作用.瘦素是一类脂肪源性细胞因子,具有多种免疫调控作用.瘦素可以通过上调RORγt的表达和转录,促进初始CD4＋T细胞向Th17细胞分化,但不影响该细胞的增殖.雷帕霉素哺乳动物靶位（mTOR）可以调控初始CD4＋T细胞的分化方向,mTORC1和mTORC2分别调节不同Th亚群的生成.研究瘦素系统与Th17细胞的关系和调控机制,将有助于通过靶向瘦素系统和AKT-mTOR信号通路来调控病理环境中的Th17细胞的免疫应答,可以为疾病的治疗提供新思路和新策略.     

肥胖与瘦素

肥胖的病因和发病机制尚未完全明了,其病因相当复杂,主要有环境因素和遗传因素,而近7年来对瘦素在调节体脂方面作用的研究,为认识肥胖提供更多的依据,本文对瘦素,瘦素受体以及瘦素的节律性分泌与肥胖的关系进行简要的综述,同时对运用瘦素治疗肥胖的意义前景做了展望。     

Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection

Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune–endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi-infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection.     

Leptin regulates the proliferation and apoptosis of human endometrial epithelial cells

The biological functions of leptin in the human endometrial epithelium were investigated using the human endometrial epithelial cell line, HHUA. Specifically, the effects of leptin on the proliferation and apoptosis of HHUA cells induced by treatment with anti-Fas IgM or anticancer drugs were examined. RT-PCR detected the expression of four leptin receptor isoform mRNAs in the cells and flow cytometric analysis revealed cell surface expression of the leptin receptor molecules. Leptin stimulated HHUA cell proliferation in a dose-dependent manner at concentrations below the normal serum leptin level. Leptin enhanced anti-Fas IgM-mediated growth inhibition and DNA fragmentation, but did not enhance the expression of either Fas antigen or Fas ligand. Moreover, leptin had no effect on anticancer drug-induced apoptosis. Based on these results, leptin at a physiological serum concentration, may regulate the remodeling of the human endometrial epithelium by stimulating cell proliferation and enhancing the Fas-specific intracellular apoptotic signaling pathway.     

Leptin receptor is expressed by tissue mast cells

Leptin, the adipose tissue-derived product of the obese (ob) gene, is known to function as the hormone of energy expenditure. It has also been established that leptin regulates immune and inflammatory processes. All leptin-induced biological activities depend on binding to the membrane-spanning leptin receptor (Ob-R), belonging to the class I cytokine receptor family. The available data relating to the Ob-R on mature mast cells (MCs), and consequently leptin significance in the modulation of MC activity within the tissue, are limited. Immunohistochemistry was used to establish Ob-R expression by MCs in the mesenteric adipose tissue. Flow cytometry and confocal microscopy were used to evaluate both constitutive and leptin-induced expression of Ob-R on freshly isolated peritoneal MCs. MCs in the mesenteric adipose tissue and native peritoneal MCs express Ob-R constitutively. Additionally, leptin influences its receptor expression on these cells. Leptin at lower concentrations caused Ob-R expression increase both at the cell surface and in the cell interior. MC stimulation with higher concentrations of leptin results in a decline of Ob-R from the cell surface and significant enhancement of this receptor not only in the nuclear region but also in the endoplasmic reticulum. In conclusion, one can be assumed that leptin regulates MC activity within tissues. These findings might provide an additional link among the leptin, innate immune function, and inflammatory processes and diseases.     

Leptin in the Pathophysiology of Human Obesity and the Clinical Potential of Leptin-Based Therapy

Leptin is a circulating hormone that is secreted in proportion to fat mass. It can reduce bodyweight by activating signalling molecules in the brain. Leptin appears to affect bodyweight primarily by decreasing food intake; there is no direct evidence that it significantly influences energy expenditure in humans. Its discovery in 1994 raised the possibility that it may be a useful, satiety-inducing, anti-obesity drug. However, treating obese patients with leptin alone does not induce substantial bodyweight loss because most obese patients are insensitive to leptin and are not leptin deficient. In combination with diet therapy, however, leptin treatment has the potential to eliminate the dramatic fall in circulating leptin levels (and the subsequent increase in hunger) caused by calorie restriction. Used in this manner, leptin may play a very useful role in the maintenance of bodyweight loss. In the future, leptin analogues and the development of compounds that increase leptin sensitivity may also prove to be valuable therapeutic approaches for obesity.     

The thymoprotective function of leptin is indirectly mediated via suppression of obesity

Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus.     

Acute physical exercise increases PI3K-p110α protein content in the hypothalamus of obese mice

The anatomy of the hypothalamus includes many nuclei and a complex network of neurocircuits. In this context, some hypothalamic nuclei reside closer to the blood-brain barrier, allowing communication with the peripheral organs through some molecules, such as leptin. Leptin is considered the main adipokine for energy homeostasis control. Furthermore, leptin signalling in the hypothalamus can communicate with insulin signalling through the activation of phosphoinositide 3-kinase (PI3k). Previous data suggest that isoforms of PI3k are necessary to mediate insulin action in the hypothalamus. However, obese animals show impairment in the central signalling of these hormones. Thus, in the current study, we evaluated the role of acute exercise in the leptin and insulin pathways in the hypothalamus, as well as in food intake control in obese mice. Although acute physical exercise was not able to modulate leptin signalling, this protocol suppressed the increase in the suppressor of cytokine signalling 3 (SOCS3) protein levels. In addition, acute exercise increased the content of PI3k-p110α protein in the hypothalamus. The exercised animals showed a strong tendency to reduction in cumulative food intake. For the first time, our results indicate physical exercise can increase PI3k-p110α protein content in the hypothalamus of obese mice and regulate food intake.     

A key role of leptin in the control of regulatory T cell proliferation

We report here that leptin can act as a negative signal for the proliferation of human naturally occurring Foxp3(+)CD4(+)CD25(+) regulatory T (T(reg)) cells. Freshly isolated T(reg) cells produced leptin and expressed high amounts of leptin receptor (ObR). In vitro neutralization with leptin monoclonal antibody (mAb), during anti-CD3 and anti-CD28 stimulation, resulted in T(reg) cell proliferation, which was interleukin-2 (IL-2) dependent. T(reg) cells that proliferated in the presence of leptin mAb had increased expression of Foxp3 and remained suppressive. The phenomena appeared secondary to leptin signaling via ObR and, importantly, leptin neutralization reversed the anergic state of the T(reg) cells, as indicated by downmodulation of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and the phosphorylation of the extracellular-related kinases 1 (ERK1) and ERK2. Together with the finding of enhanced proliferation of T(reg) cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases.     

Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation

Nutritional status has a major impact on the immune response and this is in part mediated by leptin, a pro-inflammatory cytokine. Preliminary data suggest that antagonism of leptin may offer a therapeutic approach for the treatment of some inflammatory disorders. We have tested monoclonal antibodies (mAbs) to the human leptin receptor (ObR) for antagonist activity using a leptin signalling bioassay. We identified a mAb, 9F8, which demonstrated dose-dependent antagonist activity in the leptin bioassay. Specificity of the mAb for ObR was confirmed using a plate binding assay. The 9F8 mAb displaced leptin binding to human ObR and enzymatically generated Fab fragments of 9F8 retained antagonist activity. Therefore the Fab fragment of 9F8 was cloned and recombinant 9F8 Fab (rFab) was purified from E. coli periplasmic fraction using a C-terminal His tag. Purified 9F8 rFab bound to human ObR and exhibited leptin antagonist activity. In vitro studies demonstrated that the 9F8 mAb inhibited leptin induced TNF-alpha production from human monocytes and anti-CD3 mAb induced proliferation of human T cells in PBMC culture. In conclusion, this study has identified a mAb to the human leptin receptor which inhibits leptin signalling and acts as a leptin antagonist in vitro.     

Up-regulation of vascular endothelial growth factor and down-regulation of pigment epithelium-derived factor messenger ribonucleic acid levels in leptin-exposed cultured retinal pericytes

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor and its vitreous levels were shown to be elevated in patients with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the role of leptin in diabetic retinopathy is not fully understood. Since pericyte loss and dysfunction have been considered to be one of the characteristic changes of the early phases of diabetic retinopathy, we investigated the effects of leptin on the growth and function of bovine cultured retinal pericytes. Although it did not affect cell growth, leptin significantly up-regulated pericyte messenger ribonucleic acid levels of an endogenous angiogenic stimulator, vascular endothelial growth factor (VEGF). Leptin was also found to significantly inhibit gene expression of pigment epithelium-derived factor (PEDF), the most potent angiogenesis inhibitor in the mammalian eye, in pericytes. The present study suggests that leptin might elicit angiogenesis through VEGF induction as well as PEDF suppression in pericytes and could thus be involved in the development and progression of diabetic retinopathy, especially in obese insulin-resistant patients.