Volume 43 Issue 6
Jan.  2020
Article Contents


PET receptor imaging on neurofunctional changes in obesity

  • Obesity prevalence increases worldwide, and the risk of various correlated diseases consistently grows. Although alterations in brain structure and regional activation pattern of obese individuals were widely explored in MRI and functional MRI studies, they remain incompletely understood at the molecular level. Receptor imaging with PET has been applied in obesity studies given its in vivo access to reveal brain receptor functional alterations. This article provides an overview on the role of PET brain receptor imaging in obesity.
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PET receptor imaging on neurofunctional changes in obesity

    Corresponding author: Mei Tian, meitian@zju.edu.cn
  • Department of Nuclear Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China

Abstract: Obesity prevalence increases worldwide, and the risk of various correlated diseases consistently grows. Although alterations in brain structure and regional activation pattern of obese individuals were widely explored in MRI and functional MRI studies, they remain incompletely understood at the molecular level. Receptor imaging with PET has been applied in obesity studies given its in vivo access to reveal brain receptor functional alterations. This article provides an overview on the role of PET brain receptor imaging in obesity.


  • 肥胖是人体内脂肪堆积过多进而可能损害人体健康的一种慢性代谢性疾病[1]。世界卫生组织指出,截至2016年全球超重成年人已超过19亿,其中肥胖人口超过6.5亿[2]。肥胖主要是由食物摄入过多、体力活动缺乏或遗传因素导致[3],少数是由内分泌失调、药物不良反应或精神障碍引起[4]。肥胖可严重影响人体健康,增加多种疾病的发生风险,特别是心血管疾病、2型糖尿病、阻塞性睡眠呼吸暂停综合征、某些类型的癌症和抑郁症,另外,肥胖也是骨质疏松的危险因素之一[5-7]。体重指数(body mass index, BMI)是将人的体重(kg)除以身高(m)的平方得到的数值,常用于衡量个体的营养状况。BMI介于25~30 kg/m2被定义为超重,高于30 kg/m2被定义为肥胖[8]。MRI在肥胖人群中的应用局限于大脑解剖的改变及体内脂肪组织的蓄积程度[9],功能MRI主要利用食物线索评估饮食相关脑区的激活强度。而PET受体显像能够通过对特定受体的成像获得受体分子水平的信息,反映了正常体重人群和肥胖人群中枢神经系统功能的差异,揭示人类饮食行为背后的神经调控机制,为肥胖防治带来新的突破[10-11]。笔者就近年来PET受体显像在肥胖人群神经功能成像中的作用进行综述。

  • 1.   脑受体显像基础
    • PET可利用放射性核素标记的配体与脑内某些高亲和力的受体产生特异性结合,反映脑内神经受体的空间分布、密度以及亲和力,具有高特异度及高灵敏度[12-13],PET还可以时空动态地观察神经受体功能的改变[14]。PET放射性标记的配体需满足以下条件:①标记稳定性好;②能快速通过血脑屏障并与靶受体结合;③对特定的受体具有高亲和力和高选择性,并且与不含靶受体的脑组织的非特异性结合率低[15]。目前研究较多的神经受体显像包括多巴胺受体显像、去甲肾上腺素转运蛋白(norepinephrine transporter,NET)显像和μ-阿片类受体(μ-opioid receptor,MOR)显像等。

    2.   神经受体显像在肥胖人群神经功能成像中的作用

      2.1.   多巴胺受体显像

    • 多巴胺是一种能够调节食物奖赏性能的神经递质[16]。多巴胺受体主要分为5个亚型:D1受体、D2受体、D3受体、D4受体和D5受体。目前研究主要集中在D2和D3受体,其显像剂主要包括11C-雷氯必利(11C-raclopride)、18F-fallypride和11C-(+)-4-丙基-9羟基萘恶嗪(11C-(+)-PHNO)。多巴胺D2、D3受体显像结果表明,肥胖程度与多巴胺受体结合力之间的相关性呈二次函数变化趋势[17]:对于超重至轻度肥胖人群,D2、D3受体结合力上升,并且与BMI呈明显的正相关[18-19]。行减肥手术7周后,随着肥胖人群体重的下降,尾状核、壳核、下丘脑、黑质、内侧丘脑和杏仁核中D2受体结合力减低[20]。一项11C-(+)-4-丙基-9羟基萘恶嗪(11C-(+)-PHNO)PET联合功能MRI的研究发现,BMI与D2、D3受体结合力呈正相关,同时与背侧纹状体激活强度呈负相关,但两者之间并无明显关联[18]。对于重度肥胖人群,D2、D3受体结合力降低,且与BMI呈明显负相关[21-23]。重度肥胖人群行减肥手术6周后,腹侧纹状体、尾状核和壳核中D2受体结合力明显上升[24]。但也有研究结果指出,肥胖与纹状体中的D2受体结合力并无明显的相关性[25],这可能与研究中受试者的肥胖程度较低有关。

      有研究者通过18F-FDG和11C-雷氯必利PET显像发现,背外侧前额叶、内侧眶额叶、前扣带回和躯体感觉皮质的葡萄糖代谢与纹状体的D2受体结合力呈正相关,提示纹状体的D2受体结合力的下降可能通过调节纹状体-前额叶通路导致过度进食,同时通过控制纹状体-躯体感觉皮层通路调节食物特性[23]。另有研究团队用18F-fallypride PET显像检测了肥胖人群空腹状态下胰岛素、瘦素、酰基生长素、BMI和胰岛素敏感指数与D2受体结合力之间的相关性,结果发现:在尾状核、壳核、杏仁核和颞叶,D2受体结合力与酰基生长素水平存在明显的负相关;在尾状核中,BMI和瘦素水平与D2受体结合力呈正相关;胰岛素敏感指数与腹侧纹状体中的D2受体结合力呈负相关,而胰岛素水平与D2受体结合力之间并无明显相关性[26]。该研究结果表明肥胖人群脑内多巴胺转运功能障碍与在外周合成的、饮食相关的激素关系密切。

    • 2.2.   NET显像

    • 近年来的研究表明,去甲肾上腺素在调节饮食行为及肥胖形成中也有一定的作用[27]。NET是一种位于肾上腺素能神经突触前膜上的单胺转运蛋白,其功能是调节去甲肾上腺素神经突触的结合力。11C-甲基瑞波西汀是PET神经受体显像中应用较成熟的NET显像剂。丘脑是激动神经环路的重要中继站,调节肥胖人群对食物摄入的反应[28]。研究发现肥胖人群NET的结合力在丘脑中明显降低[29],也有研究发现NET的结合力与BMI之间可呈正相关[平均BMI为(42.5±3.7)kg/m2[30]]、无相关性[平均BMI为42.4 kg/m2[31]]或者负相关[平均BMI为(33.2±9.7)kg/m2[32]、(34.7±2.6)kg/m2[29]]。一项11C-甲基瑞波西汀PET联合功能MRI的研究发现,下丘脑NET结合力越低,BMI越高,同时下丘脑与前岛脑、额岛盖及内侧眶额叶之间的连接越强[32]。因此笔者推测,与多巴胺受体相似,NET的结合力与BMI之间的相关性可能呈二次函数变化趋势,或者说多巴胺和去甲肾上腺素在肥胖人群的神经功能改变机制中有联合作用。


    • 2.3.   MOR显像

    • 大脑中内源性阿片类系统参与调节激励动机和享乐功能,当人们食用可口食物时也会产生愉悦的感觉[35]。阿片类受体(opioid receptor,OR)主要分为3种亚型:MOR、κ-OR和δ-OR。目前研究较多的OR显像剂为11C-卡芬太尼(11C-carfentanil),主要用来评估MOR的结合力。11C-卡芬太尼PET显像结果发现,病态肥胖人群[25]及暴食症患者[36]MOR的结合力广泛降低,并且MOR结合力与BMI呈负相关。MOR结合力的降低会促进暴饮暴食的行为,使减少的愉悦感得到补偿。一项联合11C-雷氯必利和11C-卡芬太尼的PET研究证实,在病态肥胖人群中,D2受体与MOR的相互作用在腹侧纹状体中明显减弱,提示依赖OR调节的中脑-边缘多巴胺系统被选择性地破坏[37]。多巴胺与阿片类系统之间的相互作用是正常奖励回路的先决条件,因此其作用的中断可能是肥胖人群奖励回路改变的基础。


    • 2.4.   其他受体显像

    • 肥胖人群的饮食行为和体重调节过程中涉及的神经生物学过程非常复杂,5-羟色胺系统和大麻素系统在调节食欲和食物摄入中也具有重要作用。2-((2-((二甲基胺基)甲基)苯基)硫)-5-氰基苯胺(11C-DASB)PET研究结果表明,肥胖人群脑内5-羟色胺转运蛋白随着BMI的上升呈下降趋势[40-41]。大麻素受体(cannabinoid receptor,CBR)有两种亚型:CB1R和CB2R,其中CB1R是中枢神经系统中最主要的CBR亚型[42]。一项N-((1s,2s)-2-(3-氰基苯基-3-(4-(2-氟乙氧基)苯基)-1-甲基丙基)-2-甲基-2-((5-甲基吡啶)-2-基)氧基)丙酰胺)(18F-MK-9470)PET研究的结果发现,食物摄入障碍患者的调节稳态区域(下丘脑和脑干)和调节奖励系统区域(中脑、纹状体、脑岛、杏仁核和眶额皮质)中的CB1R结合力下降[43]


      显像剂 应用 病种 肥胖相关
      多巴胺受体显像 D2、 D3受体 11C-(+)-PHNO 应用于临床及科研 帕金森病、精神分裂症、药物成瘾 [18-19]
      18F-fallypride [20, 26]
      11C-raclopride [21-25]
      去甲肾上腺素转运蛋白显像 去甲肾上腺素转运蛋白 11C-MRB 主要应用于科研 抑郁症、心血管疾病 [29-34]
      μ-阿片类受体显像 μ-阿片类受体 11C-卡芬太尼 主要应用于科研 疼痛、药物成瘾、酗酒 [25, 36-39]
      5-羟色胺转运蛋白显像 5-羟色胺转运蛋白 11C-DASB 主要应用于科研 帕金森病、抑郁症、强迫症 [40-41]
      大麻素1受体显像 大麻素1受体 18F-MK-9470 主要应用于科研 精神分裂症、酗酒、亨廷顿病 [43]

      Table 1.  Target receptors, imaging agents and applications of PET brain receptor imaging

    3.   小结及展望
    • PET神经受体显像是一种无创、特异、在体、动态评估大脑神经受体功能的分子影像技术,不仅能够实现从分子水平评估肥胖人群神经功能的改变,而且还可以预测肥胖人群的减重效果。因此,PET神经受体显像是临床上研究肥胖防治的重要手段,能对肥胖及因肥胖导致的相关疾病进行早期预防和早期诊断,并且能进一步为肥胖患者的个体化治疗奠定基础。未来,随着新的神经受体显像剂的不断研发和应用,PET分子影像必定在肥胖的诊疗中发挥重要作用。

      利益冲突 本研究由署名作者按以下贡献声明独立开展,不涉及任何利益冲突。

      作者贡献声明 施可欣负责资料的整理、初稿的撰写;张晓辉、金晨涛负责论文的修改;田梅负责主题的建立、论文的审阅和定稿。

Reference (43)



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