PPARs与TLR-NF-κB信号通路

过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)属于核受体超家族,它们通过调控靶基因转录参与体内多种生理病理过程。近年来,随着药理学及临床医学对PPARs的深入研究,其潜在的抗炎效应引起了人们的广泛关注。据报道,激活PPARs是他汀类药物产生抑炎效应的实现途径之一。他汀类能够激活PPARγ并抑制LPS诱导的巨噬细胞的细胞因子表达 ^[1]。 Sugamura等^[2]的研究结论也支持该项发现,其数据显示他汀类通过激活PPARγ稳定动脉粥样硬化斑块,并且联合应用辛伐他汀与PPARγ激动剂,在抑制动脉粥样硬化斑块的治疗中显示出积极疗效。这一发现为PPARs干预多种慢性非细菌性致炎疾病如动脉粥样硬化、糖尿病等,提供了有力证据。而Toll样受体(Toll-like receptor,TLR)-核因子κB(nuclear factor,NF-κB)信号通路是人体炎症与免疫应答的主要组成部分。本文就PPARs与TLR-NF-κB信号通路在准炎症反应状态下及病理性炎症反应状态下的相互作用作一综述。     

VEGF调控肥胖小鼠棕色脂肪组织炎症反应相关基因表达及通路的研究

目的:探究VEGF对肥胖小鼠棕色脂肪组织(BAT)炎症反应相关差异基因和通路表达的影响.方法:利用可逆调节VEGF表达的小鼠模型,将其分为VEGF正常表达组(dox+)和VEGF抑制表达组(dox-)(n=10).取小鼠BAT并提取总RNA,进行RNA-Seq测序及基因功能注释(GO)和信号通路(KEGG)富集度分析;...     

PPARs在不同类型心力衰竭中作用的研究进展

<正>过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)是1990年发现的核受体超家族的成员,迄今为止共发现了3种PPARs(α、β/δ和γ)。PPARs主要在肝、脂肪、心肌等组织表达,发挥促进脂肪酸摄取、转运和氧化,参与能量代谢平衡的功能^[1]。心力衰竭(简称"心衰")时心脏重塑的机制与能量稳态直接相关^[2],随着糖尿病、高血压等代谢性疾病所致慢性心衰的发病率逐年上升,代谢调控在心衰治疗中的作用受到了广泛关注^[3-4]。     

过氧化物酶增殖物激活受体γ参与动脉粥样硬化机制研究进展

过氧化物酶增殖物激活受体γ(PPARγ)是核激素受体超家族的成员之一,是一种配体激活型转录因子,参与体内多种病理生理过程.近年研究表明,PPARγ在血管壁细胞和心肌细胞中表达,具有抗炎、抗氧化和抗增殖等多种作用.该受体激活后能调节动脉粥样硬化病理过程,参与动脉粥样硬化的免疫炎症机制,并可能对动脉粥样硬化的防治具有重要意义.研究PPARγ在动脉粥样硬化中的作用,以期对动脉粥样硬化的机制研究和免疫治疗提供理论依据.     

妊娠期糖尿病患者胎盘中PPARγ的表达和作用的研究进展

妊娠期糖尿病(gestational diabetes mellitus,GDM)是一组多基因遗传所致的异质性疾病,其发病机制涉及到糖代谢机制的每一个环节.过氧化物酶体增殖物激活受体γ(per-oxisome proliferater activated receptorγ,PPARγ)是生物体重要的代谢转录因子和脂肪生成的关键因子,在糖脂代谢中发挥着重要的调控作用,其激动剂(噻唑烷二酮类药物)广泛应用于糖尿病的治疗,但目前关于PPARγ在GDM中的研究尚少.本文将对PPARγ在GDM患者的胎盘中的表达和作用进行全面的综述,并简要提及近来的一些有关GDM患者其他组织细胞中PPARγ的表达和作用的研究,以期为PPARγ作为治疗GDM的潜在靶点的临床研究奠定理论基础.     

遗传性代谢疾病的研究进展

遗传性代谢疾病（IMD）是指由于基因突变引起酶缺陷、细胞膜功能异常或受体缺陷,致使体内相应的代谢产物不能正常代谢而出现相应的病理和临床症状的一组疾病。其临床表现复杂多样,体内任何器官系统均可受累,常导致早期夭折或终身残疾。产前诊断及新生儿筛查对其早期诊断具有重要意义;常规生化检测可为诊断提供重要线索;DNA芯片技术有望成为群体筛查的方法;过氧化物酶体增殖物激活受体（PPAR）的研究将为此类疾病的药物基因治疗另辟蹊径。     

多不饱和脂肪酸对基因表达的调控机制

多不饱和脂肪酸(PVFAs)不仅是细胞结构和功能的重要组成成分,而且对细胞生长、代谢、分化中的基因起调控作用。研究表明PUFAs可通过与肝脏核因子-4α、肝脏X受体α,β、过氧化物酶体增殖物激活受体(PPARs)等核受体直接作用,或与转录因子固醇调节元件结合蛋白1,2间接作用,以多种机制在分子水平上调节相关酶的基因转录。深化PUFAs基因调控机制的研究,对于营养、健康和医疗具有重要意义。     

PPARγ在脂肪细胞分化和糖脂代谢中的作用

肥胖症和代谢综合征已经成为危害人类健康的重要问题。过氧化物酶体增殖物激活受体(PPARs)是一类配体激活转录因子，属于细胞核激素受体超家族。PPARs的3种亚型在调节糖脂代谢中扮演关键的角色。其中，过氧化物酶体增殖物活化受体γ(PPARγ)是脂肪细胞基因表达和胰岛素细胞间信号传递的主要调节者。     

Orexin receptor type 2 agonism inhibits thermogenesis in brown adipose tissue by attenuating afferent innervation

Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.     

Quantitative image analysis in adipose tissue using an automated image analysis system: differential effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist on white and brown adipose tissue morphology in AKR obese and db/db diabetic mice

Morphometric analysis of adipocytes is widely used to demonstrate the effects of antiobesity drugs or anti-diabetic drugs on adipose tissues. However, adipocyte morphometry has been quantitatively performed by manual object extraction using conventional image analysis systems. The authors have developed an automated quantitative image analysis method for adipose tissues using an innovative object-based quantitative image analysis system (eCognition). Using this system, it has been shown quantitatively that morphological features of adipose tissues of mice treated with peroxisome proliferator-activated receptor (PPAR) agonists differ dramatically depending on the type of PPAR agonist. Marked alteration of morphological characteristics of brown adipose tissue (BAT) treated with GI259578A, a PPAR-alpha agonist, was observed in AKR/J (AKR) obese mice. Furthermore, there was a 22.8% decrease in the mean size of adipocytes in white adipose tissue (WAT) compared with vehicle. In diabetic db/db mice, the PPAR-gamma agonist GW347845X decreased the mean size of adipocytes in WAT by 15.4% compared with vehicle. In contrast to changes in WAT, GW347845X increased the mean size of adipocytes in BAT greatly by 96.1% compared with vehicle. These findings suggest that GI259578A may activate fatty acid oxidation in BAT and that GW347845X may cause adipocyte differentiation in WAT and enhancement of lipid storage in BAT.     

Peroxisome proliferator-activated receptors: new players in the field of reproduction

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily. Synthetic ligands to one family member, PPARgamma, are currently widely used as treatment for chronic diseases such as diabetes type II and other insulin resistances, e.g. as seen in polycystic ovary syndrome (PCOS). Moreover, novel approaches employing knock-out mice demonstrated that PPARgamma seems to play a key role in placental and fetal development. This review describes recent insights into the role of PPARs in human reproduction with specific reference to infertility, placental maturation and fetal development as well as disturbed pregnancy. Further, we highlight the current knowledge on synthetic ligands to PPARgamma used as a treatment in women with PCOS.     

Functional disconnection of brown adipose tissue in hypothalamic obesity in rats

The metabolic responses to electrical nerve stimulation, norepinephrine or octanoate additions were studied using continuous monitoring of NAD(P)H/NADP redox state by reflexion spectrophotometry of interscapular brown adipose tissues from control and ventromedial hypothalamic (VMH) lesioned rats. The responses to these stimuli were all greatly decreased already 3 days after VMH lesions, indicating a reduced cell capacity to oxidize free fatty acids. Measurements of interscapular brown adipose tissue composition 4–5 weeks after VMH lesions showed a decrease of both DNA concentration and total content, indicating some tissue involution.It is concluded that the involvement of the ventromedial bypothalamus in the activation of brown adipose tissue provided a possible anatomical clue concerning pathways connecting thermal and weight regulations.     

Increased weight gain and reduced activity in brown adipose tissue produced by depletion of hypothalamic noradrenaline

In chick retina, the tailed 20S molecular form of acetylcholinesterase (A12) is slowly degraded to globular forms after homogenization of the tissue in a buffer-salt-detergent solution, in the absence of EDTA. This process can be stopped by the addition of EDTA to the homogenate, prior to high speed centrifugation; however, longer delays in adding EDTA lead to lower recoveries of tailed enzyme. The rate of degradation of A12 is considerably enhanced by high speed centrifugation of this EDTA-less homogenate prior to addition of EDTA.     

Catecholaminergic innervation of interscapular brown adipose tissue in the naked mole-rat (Heterocephalus glaber)

The thermogenic potential of the interscapular brown fat pad in the naked mole-rat Heterocephalus glaber , that exhibits poikilothermic thermal responses to changing temperatures is reported. Histological and ultrastructural study of the brown fat pad showed that it consists of layers of skeletal muscle interposed between the layers of brown adipose tissue with both unilocular and multilocular adipocytes. Large numbers of mitochondria were present between and around the lipid droplets of these cells. Glyoxylic acid condensation, used to demonstrate catecholaminergic nerves, was evident in low concentrations in the connective tissue between the brown adipocytes. A 3-dimensional computer-aided reconstruction of the fat pad showed the extent and ramification of nerves and blood vessels between the adipocytes. These findings show that although the naked mole-rat is regarded as an endothermic poikilotherm, it possesses anatomical features usually found in homeothermic mammals, which are essential for thermogenesis.     

Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance

Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T₂ weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T₂* maps of BAT were obtained at multiple time points before and after administration of the β₃ adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 ± 1 mm³ versus 65 ± 3 mm³; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T₂* in healthy animals but not in mice with heart failure (24 ± 4% versus 6 ± 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright © 2016 John Wiley & Sons, Ltd.     

Peroxisome proliferator-activated receptor-gamma expression in the lung tissue of obese rats

Purpose

Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats.

Materials and Methods

Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR.

Results

PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats.

Conclusion

PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.     

Activation of peroxisome proliferator-activated receptor gamma suppresses mast cell maturation involved in allergic diseases

Background:  Mast cells play a central role in allergic and inflammatory diseases. Several reports indicated role of peroxisome proliferator-activated receptor gamma (PPARγ) on mast cell function. However, there is no report about the role of PPARγ on differentiation of mast cells from the progenitors. In this study, we investigated the role of PPARγ in regulating bone marrow-derived mast cell maturation and the therapeutic implications for mast cell-related diseases such as atopic or contact dermatitis.
Methods:  We used in vitro cell culture system for mast cell differentiation from bone marrow-progenitors using specific ligands and lentiviral-mediated short hairpin RNA of PPARγ, and in vivo murine dermatitis models.
Results:  Activation of PPARγ inhibited the maturation of bone marrow progenitors into connective tissue-type mast cells (CTMCs) through up-regulation of GATA-4 and GATA-6 resulting in a decrease in expression of histidine decarboxylase and mast cell histamine content. In comparison, the differentiation of bone marrow progenitors into CTMCs was significantly accelerated by the knockdown of PPARγ expression by lentiviral-mediated short hairpin RNA. Peroxisome proliferator-activated receptor gamma ligand administration to mice inhibited the maturation of mast cells resulting in attenuation of atopic and contact dermatitis via diminishment of the number of mature mast cells.
Conclusion:  Our results indicate that PPARγ is one of master regulators on mast cell maturation and potentially useful for the therapy in various disorders involving mast cell activation.     

白色脂肪"棕色化"调控因子FNDC5/Irisin的研究进展

肥胖是当下全球牵涉范围最广的慢性疾病,也是2型糖尿病、心脑血管疾病以及某些癌症的重要风险因素.其中"白色脂肪棕色化"是目前该领域研究的热点之一,即将体内的储存多余能量的白色脂肪组织(white adipose tissue,WAT)转变为促进消耗能量的棕色脂肪组织(brown adipose tissue,BAT).近年在肌细胞中发现的Ⅲ型纤连蛋白组件包含蛋白5(fibronectin typeⅢdomain containing 5,FNDC5)经胞外切除形成小分子多肽,名为Irisin,具有"白色脂肪棕色化"的功能.