靶向USPIO MR探针测定活体内棕色脂肪研究

Contrary to white adipose tissue (WAT) which stores up energy, brown adipose tissue (BAT) facilitates consumption of energy. It is more recently that functional human BAT (hBAT) was found in adult humans playing an important role in maintaining body metabolic efficiency. There are evidences that BAT is not only related to fat depots, but also to neoplasms, hypertension, coronary heart disease, and even the ageing process. Monitoring hBAT mass and activity has become a hot point in clinical studies. Although PET/CT was the first modality to provide the original evidence of functional adult hBAT, there are several limitations to 18F-FDGPET/CT as following: the initial metabolic substrate of BAT is believed to be free fatty acids; glucose uptake into BAT measured by 18F-FDGPET/CT can be affected under many physiologically meaningful conditions; and, PET/CT is relatively expensive and involves significant exposure of a subject to ionizing radiation and therefore cannot be used in infants, children, and healthy cohorts. An effective and simple modality or technique is needed to elucidate hBAT properties in clinical settings. Our study should innovatively combine specific BAT-targeted peptide with ultrasmall super- paramagnetic iron oxide (USPIO) to archive targeted USPIO MR probes specific to BAT, use non-ionizing and relatively inexpensive MRI to characterize hBAT mass and activity, and develop a new evaluation method of research and therapy of obesity clinically.

与白色脂肪组织储存能量相反，棕色脂肪组织(BAT)促进能量消耗，目前发现成人体内存在着具有功能的棕色脂肪组织，对维持机体能量平衡起关键作用。研究发现BAT不仅和体内脂肪堆积有关，而且还和肿瘤、高血压、冠心病，甚至衰老有关，评价BAT量和功能已成为临床研究热点。18F-FDG PET/CT是第一个证实人体存在BAT的临床有效手段，但还有许多不足：游离脂肪酸才是BAT的代谢底物；葡萄糖摄取的体内影响因素很多；18F-FDG PET/CT不是可靠的功能影像，且检查比较昂贵、有放射性，不适用青少年和健康者。临床急需测定体内棕色脂肪的简便有效的方法。本课题创新地利用特异的棕色脂肪组织靶向多肽（获国家发明专利），与超微超顺磁性氧化铁（USPIO）颗粒联结，合成棕色脂肪组织靶向的USPIO MR探针，使用无放射性、价格相对便宜的MRI，活体测定体内BAT量和功能，为临床肥胖研究和治疗提供新的评价手段。

肥胖已成为一种全球流行性疾病，肥胖增加了糖尿病、高血压、冠心病等慢性疾病的危险因素。当能量摄入超过消耗时，机体产生肥胖。众所周知，白色脂肪是能量以甘油三酯形式存在的主要部位，而棕色脂肪是哺乳动物调节性产热的主要器官。增加棕色脂肪的量、提高棕色脂肪的功能可以有效地增加能量消耗，减少白色脂肪的积聚，提高代谢，抵制肥胖、高血脂以及其它代谢疾病。18F-FDGPET/CT 是目前最常用的棕色脂肪成像方式，然而，PET/CT 成像依赖于代谢组织对葡萄糖的摄取。PET/CT仅可以对激活的棕色脂肪进行成像，而对非激活的中性状态下的棕色脂肪不敏感。PET/CT的另一个缺点是其具有电离辐射，不适用于青少年和儿童。在这项研究中，我们创新性地将棕色脂肪靶向多肽与USPIO相偶联，合成棕色脂肪靶向探针，研究该靶向探针在磁共振上活体探测棕色脂肪的应用。本研究成功合成了棕色脂肪靶向探针，验证了探针的性质，荧光结果验证了探针的成功合成。MR T2* mapping的成像结果显示靶向组棕色脂肪的T2*值降低，明显低于其它组织，差异有统计学意义（P<0.001）。普鲁士蓝染色和电镜显示了靶向探针组棕色脂肪内可见较多的铁染颗粒，而其它组织内铁染颗粒较少，证实了该靶向探针可以在磁共振上对活体内棕色脂肪进行特异性地、无创地靶向成像，为棕色脂肪活体成像提供了一种特异的、敏感的方式。并进一步分析棕色脂肪功能蛋白UCP1基因表达和蛋白活性，MR T2* mapping成像结果显示寒冷刺激组的T2*值降低，明显低于正常对照组，病理结果显示寒冷刺激组的UCP1的基因表达明显高于正常对照组，差异具有统计学意义，结果显示MRI测定的棕色脂肪组织与体内棕色脂肪组织的功能相关性较高，MRI能够较好地反应棕色脂肪的功能，为棕色脂肪的功能测定提供了一种无创地方式，并且为临床肥胖的研究和治疗提供了一种新的评估方法。