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撰文 | 郑宇含 王佳雯 张婷 马莹 李雨
编辑 | 孟美瑶
校对 | 张彦康
有些小动物看起来一派祥和
其实暗藏玄机
相同药物治疗后
特应性皮炎患者里
肥胖的与瘦的患者治疗效果相反
近期Nature发表研究揭开隐藏的玄机
肥胖能将与特应性皮炎(AD)相关的
经典2型T辅助细胞(TH2)为主
转变为以TH17为主的炎症类型
揭示了肥胖对免疫疾病的影响
Nature
1、肥胖影响炎症性疾病的病理和治疗反应
要想肥胖少烦恼,PPARγ少不了!
中文摘要
既往数十年的研究已阐明了参与调控T细胞分化的细胞信号和转录途径,为有效靶向治疗自身免疫性疾病、过敏性疾病和炎症性疾病奠定了基础。近来有研究表明,肥胖和代谢性疾病也可以影响免疫系统,但其机制和对免疫治疗的影响仍不清楚。本文中,研究人员在两种遗传过敏性皮炎小鼠模型中发现肥胖小鼠和正常小鼠表现出不同的免疫反应。进一步研究发现肥胖加剧了经典的TH2(2型辅助性T细胞)相关过敏性皮炎,并激活了TH17相关的炎症反应。研究人员还发现肥胖小鼠和正常小鼠对靶向TH2细胞因子的生物疗法具有不同的反应,在正常小鼠中靶向TH2治疗可有效缓解小鼠的过敏性皮炎病理,但却加重了肥胖小鼠的过敏性皮炎病理。经scRNA-seq与全基因组蛋白结合分析发现肥胖小鼠TH2细胞中PPARγ(过氧化物酶体增殖物激活受体-γ)活性显著低于正常小鼠。T细胞特异性敲除PPARγ后发现,将体内TH反应集中于TH2相关炎症反应并抑制异常的非TH2相关炎症反应的过程需要PPARγ参与。利用PPARγ激动剂治疗过敏性皮炎肥胖小鼠,可有效阻止TH17相关炎症病理的发展,且靶向TH2治疗也可显著缓解肥胖小鼠的炎症病理。总之,这些研究揭示了肥胖对免疫疾病的影响,并提出了一种有效治疗由肥胖引起的免疫失调的精准治疗方法。
拓展阅读
肥胖对T细胞功能的影响
参考文献:
Obesity alters pathology and treatment response in inflammatory disease
发表单位:NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA
Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
原文链接:https://www.nature.com/articles/s41586-022-04536-0
据说当天
没有一个人能优雅的走出公司大门
对此公司提出表扬!我我我可!
近期Nature发表研究
再次对运动提出表扬!
研究发现运动中产生的一种代谢物Lac-Phe
能够有效地减少实验小鼠的
食物摄入量并帮助抵御肥胖
Nature
2、一种由运动诱导的代谢物,可抑制食欲并缓解肥胖
运动减肥进行时——Lac-Phe帮你抑制食欲!
中文摘要
运动可以预防肥胖、2型糖尿病和其他心脏代谢疾病,然而,介导运动代谢获益的分子与细胞机制还不清楚。本文中,研究人员发现运动可以诱导产生Lac-Phe(N-乳酰苯丙氨酸),Lac-Phe可作为血源性信号代谢物抑制小鼠的食欲并抵抗肥胖。Lac-Phe由乳酸和苯丙氨酸结合生成,这一过程发生在CNDP2表达的细胞中,包括不同组织中的巨噬细胞、单核细胞以及其他免疫细胞与上皮细胞。在饮食诱导的肥胖小鼠中,利用药理手段促进Lac-Phe水平可降低小鼠的摄食量,但并不影响小鼠的活动量和能量消耗。在Lac-Phe长期作用下可显著降低小鼠体重,缓解肥胖并改善糖稳态。相反,利用基因敲除手段抑制Lac-Phe生物合成过程,可增加小鼠在训练后的摄食量,加剧小鼠的肥胖。最后,研究人员在人体和赛马中也发现运动后血液中Lac-Phe活性显著升高,这表明Lac-Phe在多种物种和多种运动模式中均可作为运动的分子效应因子。总之,这些研究发现了一种保守的由运动诱导的代谢产物,它可调节机体食欲并影响整体能量平衡。
拓展阅读
一作: Veronica L. Li: PI:Jonathan Z. Long
发表单位:Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
Abstract
原文链接:https://www.nature.com/articles/s41586-022-04828-5
猫猫的喜好你猜不到
但质子载体的作用机制
似乎有迹可循
近期Nature发表研究揭示
线粒体解偶联剂通过激活
ADP/ATP载体(AAC)和
解偶联蛋白1(UCP1)诱导H+泄漏
Nature
3、线粒体解偶联剂通过激活AAC和UCP1诱导质子泄漏
线粒体解偶联剂促脂肪产热的机制大揭秘
中文摘要
线粒体由于H+泄露(lH)穿过内膜而产生热量。lH是由长链脂肪酸作用于棕色脂肪UCP1(解偶联蛋白1)或其他组织AAC(ADP/ATP载体)而引起的,但其机制尚不清楚。尽管缺乏靶向UCP1和AAC的lH药理激活剂,一些质子载体如DNP(2,4-二硝基苯酚)和FCCP(氰化物-4-(三氟甲氧基)苯腙)可诱导lH。虽然在动物模型中质子载体表现出治疗肥胖、糖尿病和脂肪肝的潜力,但由于其非选择性增加所有生物膜的H+导电性并产生副作用,质子载体在治疗人类疾病的临床应用有限。本文中,研究人员直接测量了DNP、FCCP和其他常见质子载体诱导的lH,发现其依赖于AAC和UCP1。研究人员对AAC分子结构进行计算分析以确定质子载体和长链脂肪酸的结合位点,发现它们与预测的ADP/ATP结合位点重叠。此外,研究人员还建立了一个数学模型,提出了通过AAC促进解偶联依赖的lH的机制。总之,这些研究结果发现常见的质子载体解偶联剂均是靶向AAC和UCP1的lH激活剂,为开发靶向AAC和UCP1的新型特异性高的lH激活剂奠定了基础。
拓展阅读
AAC(ADP/ATP转运蛋白)和UCP是最早被发现的线粒体转运蛋白家族成员。这两种转运蛋白都与线粒体质子泄露密切相关。AAC主要负责将线粒体中的ATP转运进入细胞质供细胞利用,同时将细胞质中的ADP转运进线粒体。有研究报道,AAC除介导ATP/ADP转运外,还可介导线粒体质子泄露,并且该过程受AAC介导的ADP/ATP转运负向调节,因此,AAC可能在维持细胞产能和产热平衡中起重要作用。UCP是通过膜电位驱动H+或OH-转运的转运体。UCP与AAC具有相似的分子量且都能结合核苷酸,但是对于ACC来说核苷酸是底物,而对于UCP来说核苷酸是抑制剂。除此之外UCP1是棕米色脂肪特异表达的蛋白,负责调控棕米色脂肪细胞线粒体的质子泄露,而ACC主要负责调控不表达UCP1的组织的质子泄露,因此对于全身的代谢调节来说更重要。
质子载体如FCCP,DNP可以通过转运质子来消除线粒体内膜两侧的质子浓度差和电化学势,从而起到将电子传递产生的质子浓度差和ATP合成解偶联。而解偶联剂不只是质子载体,还包括离子载体如缬氨霉素,可以通过携带K+进入线粒体内膜从而消除线粒体内膜两侧的电化学梯度,也可以起到解偶联的作用。
Abstract
Mitochondria generate heat due to H leak (I+H) across their inner membrane. I+H results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat and ADP/ATP carrier (AAC) in other tissues, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of I+H through UCP1 and AAC is lacking, I+H is induced by protonophores such as 2,4-dinitrophenol(DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone(FCCP). Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models, their clinical potential for treating human disease is limited due to indiscriminately increasing H conductance across all biological membranes+ and adverse side effects. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.
原文链接:https://www.nature.com/articles/s41586-022-04747-5
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