炎症和肥胖

近来研究表明：脂肪和巨噬细胞之间存在惊人的相似之处。这个结论引发人们猜测：炎症反应也许是连接肥胖和糖尿病的桥梁。     

肥胖与慢性炎症的研究进展

肥胖常伴随着一系列代谢综合征的发生,肥胖引起的慢性炎症因为与各种代谢综合征的密切联系而成为目前的研究热点。慢性炎症的发生很复杂,涉及多个组织、器官和系统,并且炎症的发生会反过来影响组织的功能。目前针对慢性炎症发生机制的研究结果显示脂肪因子和免疫系统、内质网应激、细胞自噬作用以及内毒素的作用等形成的信号网络参与了慢性炎症的触发和发展。本文就慢性炎症与肥胖关联的几种可能发生机制的最新研究进展作一简要综述。     

肥胖与脂肪组织巨噬细胞的研究进展

肥胖被认为是一种慢性促炎症疾病。近年来巨噬细胞在肥胖的发生过程中起的重要作用越来越被研究者们所重视。研究发现脂肪组织巨噬细胞(ATMs)的极化和招募在肥胖的发生过程中扮演着重要角色:在肥胖的脂肪组织中,巨噬细胞M1/M2的比例出现失衡即M1促炎巨噬细胞比例上调M2抑炎巨噬细胞比例下调导致脂肪组织慢性炎症;脂肪组织的局部炎症发生时周边组织巨噬细胞招募至脂肪组织也能够促进肥胖的发展进程。本文就肥胖的发生与脂肪组织巨噬细胞的极化和招募的关系作一综述。     

不同强度电针对肥胖大鼠脂肪组织炎症相关因子的影响

探讨不同强度电针对肥胖大鼠脂肪组织核因子-κBp65(NF-κBp65)、单核细胞趋化蛋白-1(MCP-1)和肿瘤坏死因子-α(TNF-α)的作用差异.将SD大鼠随机分为普通饮食组、高脂饮食组、5 V电针组、2.5 V电针组,除普通饮食组外其余各组大鼠均饲以高脂饲料.取"足三里"、"三阴交"穴,不同强度电针治疗14 d后,用蛋白质印迹技术(Western blot)检测肥胖大鼠附睾脂肪组织NF-κBp65的表达,酶联免疫吸附法(ELISA)检测肥胖大鼠附睾脂肪组织MCP-1、TNF-α的含量.研究发现两电针组肥胖大鼠体重、Lee’s指数、脂肪组织中NF-κBp65表达、MCP-1和TNF-α含量较高脂饮食组显著降低(P<0.01),5 V电针组较2.5 V电针组下降效果更为明显(P<0.01,P<0.05).结果表明电针可改善肥胖脂肪组织炎症反应状态,减轻肥胖大鼠体重,且5 V电针组效果优于2.5 V电针组.     

青蒿素类化合物与肥胖诱导的代谢性炎症

青蒿素类化合物是治疗疟疾的首选药物,具有高效、速效、低毒和安全的特点。近三十年来,大量研究结果证明青蒿素类化合物具有抗炎和免疫调节功能;这些研究主要集中于自身免疫性疾病,如类风湿性关节炎、全身性红斑狼疮、哮喘病和过敏反应等。最新研究表明,青蒿素类化合物可通过促进白色脂肪棕色化和增强棕色脂肪功能,起到预防肥胖的作用。作为肥胖过程中免疫细胞和炎症状况变化显著的脂肪组织,青蒿素类化合物是否参与其中的免疫炎症调节以及在该过程中发挥的潜在作用有待进一步实验的验证。本文对已有的青蒿素类化合物在抗炎和免疫调节方面的报道进行总结,并对青蒿素类化合物在改善肥胖诱导代谢性炎症方面的潜在应用进行展望。     

脂肪组织中巨噬细胞在肥胖过程中的作用及其调控机制

肥胖是一个全球性的健康问题,世界上三分之一的成年人口出现超重或肥胖现象,儿童肥胖的比例也在逐年上升。超重或肥胖会增加患严重慢性疾病的风险,例如II型糖尿病、高血压、心血管疾病和哮喘等。越来越多的证据表明,慢性炎症是肥胖的一个重要特征,持续性炎症可以导致肥胖和肥胖相关的代谢疾病。因此,肥胖现在被认为是一种与代谢紊乱相关的低度慢性炎症疾病。了解脂肪组织中免疫细胞与脂肪沉积的关系可能对开发肥胖及相关代谢疾病的治疗策略具有重要意义。巨噬细胞是脂肪组织中含量最多的免疫细胞,在炎症的诱导和消退方面发挥重要作用。本文概述了脂肪组织中巨噬细胞在肥胖过程中的响应,及巨噬细胞对脂肪细胞的调控机制进而影响肥胖的发生发展。在此基础上,总结出巨噬细胞参与肥胖调控的4条主要途径：(1)巨噬细胞通过分泌外泌体进入邻近脂肪细胞内,通过干扰PPARg或Nadk的表达,引起脂肪沉积的降低或增加;(2)巨噬细胞通过M1型和M2型之间的极化,引起脂肪沉积的变化;(3)巨噬细胞通过分泌调控因子引起脂肪组织中交感神经纤维变化,进而调控脂质沉积;(4)巨噬细胞通过捕获外源线粒体,来调控脂质沉积。巨噬细胞变化作为肥胖过程中关键事件,...     

肥胖患者载脂蛋白M水平及其与炎症因子的关系研究

目的：观察肥胖患者载脂蛋白M水平并探讨其与炎症因子的关系。方法：58例体重正常者和36例肥胖患者常规测量体重、身高,计算体重指数,抽取空腹静脉血检测血脂、血浆载脂蛋白M（apoM）、白细胞介素-6（IL-6）、C反应蛋白（CRP）、肿瘤坏死因子α（TNF—α）。结果：肥胖患者血浆apoM、高密度脂蛋白胆固醇（HDL-C）降低（P〈0．05）,IL-6、TNF—α、CRP水平升高（P〈0．05）,肥胖患者血浆αpoM与HDL-C正相关,血浆αpoM与IL-6、TNF—α、CRP水平负相关。结论：肥胖患者血浆apoM显著降低,αpoM水平与CRP、TNF-α、IL-6水平密切相关,apoM可能受到这些炎症因子的调控。     

肥胖患者载脂蛋白M水平及其与炎症因子的关系研究

目的:观察肥胖患者载脂蛋白M水平并探讨其与炎症因子的关系。方法:58例体重正常者和36例肥胖患者常规测量体重、身高,计算体重指数,抽取空腹静脉血检测血脂、血浆载脂蛋白M(apoM)、白细胞介素-6(IL-6)、C反应蛋白(CRP)、肿瘤坏死因子α(TNF-α)。结果:肥胖患者血浆apoM、高密度脂蛋白胆固醇(HDL-C)降低(P<0.05),IL-6、TNF-α、CRP水平升高(P<0.05),肥胖患者血浆apoM与HDL-C正相关,血浆apoM与IL-6、TNF-α、CRP水平负相关。结论:肥胖患者血浆apoM显著降低,apoM水平与CRP、TNF-α、IL-6水平密切相关,apoM可能受到这些炎症因子的调控。     

青蒿素类化合物与肥胖诱导的代谢性炎症北大核心CSCD

青蒿素类化合物是治疗疟疾的首选药物,具有高效、速效、低毒和安全的特点。近三十年来,大量研究结果证明青蒿素类化合物具有抗炎和免疫调节功能;这些研究主要集中于自身免疫性疾病,如类风湿性关节炎、全身性红斑狼疮、哮喘病和过敏反应等。最新研究表明,青蒿素类化合物可通过促进白色脂肪棕色化和增强棕色脂肪功能,起到预防肥胖的作用。作为肥胖过程中免疫细胞和炎症状况变化显著的脂肪组织,青蒿素类化合物是否参与其中的免疫炎症调节以及在该过程中发挥的潜在作用有待进一步实验的验证。本文对已有的青蒿素类化合物在抗炎和免疫调节方面的报道进行总结,并对青蒿素类化合物在改善肥胖诱导代谢性炎症方面的潜在应用进行展望。     

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr^−/− recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.     

Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity

Women of reproductive age are protected from metabolic disease relative to postmenopausal women and men. Most preclinical rodent studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of a similar protection observed in female mice. How sex differences in obesity-induced inflammatory responses contribute to these observations is unknown. We have compared and contrasted the effects of high fat diet-induced obesity on glucose metabolism and leukocyte activation in multiple depots in male and female C57Bl/6 mice. With both short term and long term high fat diet, male mice demonstrated increased weight gain and CD11c⁺ adipose tissue macrophage content compared with female mice despite similar degrees of adipocyte hypertrophy. Competitive bone marrow transplant studies demonstrated that obesity induced a preferential contribution of male hematopoietic cells to circulating leukocytes and adipose tissue macrophages compared with female cells independent of the sex of the recipient. Sex differences in macrophage and hematopoietic cell in vitro activation in response to obesogenic cues were observed to explain these results. In summary, this report demonstrates that male and female leukocytes and hematopoietic stem cells have cell-autonomous differences in their response to obesity that contribute to an amplified response in males compared with females.     

Age‐associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro‐atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr ^−/− recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.     

The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2^ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2^ΔLysM macrophages and their floxed controls. Furthermore, Ucp2^ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2^ΔLysM and Ucp2^fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2^ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2^fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.     

褐色脂肪组织代谢与肥胖

肥胖是由于机体能量储存与消耗的失衡而产生的.褐色脂肪组织通过产热的形式,能够将体内过多的能量释放出来,以减少能量积累,避免造成肥胖.现从褐色脂肪组织的结构、分布、功能以及调控机制等方面,对褐色脂肪组织与肥胖症的关系作一综述,旨在为防治肥胖症及相关疾病寻找理论基础和实验依据.     

Fas activates lipolysis in a Ca2+-CaMKII-dependent manner in 3T3-L1 adipocytes

Fas (CD95) is a member of the tumor necrosis factor (TNF) receptor superfamily and plays a crucial role in the induction of apoptosis. However, like TNF, Fas can induce nonapoptotic signaling pathways. We previously demonstrated that mice lacking Fas specifically in adipocytes are partly protected from diet-induced insulin resistance, potentially via decreased delivery of FAs to the liver, as manifested by lower total liver ceramide content. In the present study, we aimed to delineate the signaling pathway involved in Fas-mediated adipocyte lipid mobilization. Treatment of differentiated 3T3-L1 adipocytes with membrane-bound Fas ligand (FasL) significantly increased lipolysis after 12 h without inducing apoptosis. In parallel, Fas activation increased phosphorylation of ERK1/2, and FasL-induced lipolysis was blunted in the presence of the ERK-inhibitor U0126 or in ERK1/2-depleted adipocytes. Furthermore, Fas activation increased phosphorylation of the Ca²⁺/calmodulin-dependent protein kinases II (CaMKII), and blocking of the CaMKII-pathway (either by the Ca²⁺ chelator BAPTA or by the CaMKII inhibitor KN62) blunted FasL-induced ERK1/2 phosphorylation and glycerol release. In conclusion, we propose a novel role for CaMKII in promoting lipolysis in adipocytes.     

TLRs、慢性炎症与肿瘤

Toll样受体是新发现的先天性免疫的病原模式识别受体,在机体抵抗外来病原生物入侵上起关键的作用。除了抵抗外来病原生物入侵外, Toll样受体现在也被认为与某些自身免疫性疾病、肿瘤和某些病因不明的疾病的发病有关。慢性炎症被认为在不同层面促进某些肿瘤的发生和发展,其中之一就是慢性炎症通过免疫抑制导致免疫系统对肿瘤细胞无反应,这种免疫抑制也与 Toll样受体有关。     

肥胖诱发胰岛素抵抗的炎性机制

肥胖可诱发一系列慢性代谢性疾病,如2型糖尿病、血脂障碍、高血压和非酒精性脂肪肝等.这些疾病构成了当今世界人类健康的极大威胁.胰岛素抵抗是这些疾病的共有特征.胰岛素抵抗的发生与慢性低度系统炎性密切相关,涉及多条炎性信号通路的激活和胰岛素信号转导的缺陷.本文综述了肥胖、炎性与胰岛素抵抗之间的本质联系,以及肥胖诱发胰岛素抵抗的炎性机制,以期为肥胖相关疾病的防治提供重要参考.     

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Obesity is accompanied by adipocyte death and accumulation of macrophages and mast cells in expanding adipose tissues. Considering the differences in biological behavior of fat found in different anatomical locations, we explored the distribution of mast cells, solitary macrophages, and crown-like structures (CLS), the surrogates for dead adipocytes, in subcutaneous and abdominal visceral fat of lean and diet-induced obese C57BL/6 mice. In fat depots of lean mice, mast cells were far less prevalent than solitary macrophages. Subcutaneous fat contained more mast cells, but fewer solitary macrophages and CLS, than visceral fat. Whereas no significant change in mast cell density of subcutaneous fat was observed, obesity was accompanied by a substantial increase in mast cells in visceral fat. CLS became prevalent in visceral fat of obese mice, and the distribution paralleled mast cells. Adipose tissue mast cells contained and released preformed TNF-α, the cytokine implicated in the pathogenesis of obesity-linked insulin resistance. In summary, subcutaneous fat differed from visceral fat by immune cell composition and a lower prevalence of CLS both in lean and obese mice. The increase in mast cells in visceral fat of obese mice suggests their role in the pathogenesis of obesity and insulin resistance.