【作者】 苗青；

【导师】 李益明；

【作者基本信息】 复旦大学 ， 内科学， 2011， 博士

【摘要】 肥胖已成为世界范围内危害人类健康的主要疾病之一,与高血压、冠心病、脑血管意外、2型糖尿病、血脂紊乱、肿瘤等众多疾病密切相关。近年来的研究显示成人体内存在着活性棕色脂肪组织(Active brown adipose tissue, aBAT),其通过调节性产热对人体的能量平衡起重要作用,可能成为肥胖及其他代谢紊乱防治的新靶点。目前有关中国成人aBAT阳性率的研究很少,而国内外几乎所有的研究对象均为肿瘤患者,不能代表健康人群；并且所有的临床研究仅对BAT出现者的基线特征如性别、年龄、体重指数(Body mass index, BMI)、有无肿瘤史、空腹血糖水平(Fasting plasma gluscose, FPG)等进行了分析,但对可能影响去甲肾上腺素、甲状腺素分泌的因素如烟酒史、运动习惯、甲状腺疾病等未进行分析。另外成人不同BAT活性及甲状腺功能状态与脑功能的关系尚不清楚,需要通过前瞻性研究进一步明确。因此,本研究通过动态观察分析不同人群、不同BAT活性和甲状腺功能状态下的各项特征差异,对BAT活性相关因素及其中枢机制进行了初步的分析和探索,为今后的继续研究奠定了一定的基础。第一部分中国成人棕色脂肪阳性率及其相关因素分析[目的]比较存在aBAT的肿瘤患者和健康体检者的特征差异,并在此基础上寻找影响BAT活性的相关因素。[方法]回顾复旦大学附属华山医院PET中心2006年7月1日至2010年6月30日期间31088名行氟脱氧葡萄糖标记的正电子发射断层扫描(Fluorine-18-fluorodeoxyglucose positron-emission tomography and computed tomography,18F-FDG PET-CT)检查的受检者资料。根据PET-CT的原始图像找出存在aBAT的受检者并分析其基本信息和临床特征。[结果]aBAT主要分布于颈部至纵隔、脊柱旁的中轴部位。在31088名受检者中有410名(1.32%)存在aBAT,其阳性率低于国外相关报道(5.37%)。其中肿瘤者1 46名,占肿瘤人群的1.01%；体检者264名,占体检人群的1.58%,两组的阳性率有显著差异(P<0.05)。无论是在总体人群(2.36%[273/11570]vs.0.70%[137/19518],P<0.0001),还是在肿瘤人群(1.59%vs.0.61%,P<0.0001)或体检人群(3.16%vs.0.77%,P<0.0001)中,女性的aBAT阳性率均明显高于男性。通过对肿瘤人群的单因素回归分析发现女性(P=0.0005)、年龄分层最年轻(<39.7岁,P=0.0077)、BMI最小(P<0.0001)、无吸烟史(P<0.0001)、饮酒较少(P=0.0015)、适度运动(P=0.0309)及无脂肪肝(P=0.0003)的患者更易出现aBAT。而在健康体检人群中,除了运动(P=0.1937)与aBAT无显著相关性外,其余结果与肿瘤人群相似。在多因素分析校正年龄和性别后发现,与肿瘤人群aBAT仍显著相关的因素有BMI、吸烟和运动；与体检人群仍显著相关的有BMI、吸烟和甲状腺高代谢。【结论】中国成人的aBAT阳性率为1.32%,肿瘤人群的阳性率低于健康体检人群。棕色脂肪活性不仅和性别、年龄、气温等因素有关,还和BMI、吸烟、运动及甲状腺相关疾病等因素显著相关,提示其在调节人体能量代谢中可能起重要作用。第二部分甲状腺功能状况对中国成人棕色脂肪和肌肉糖代谢的影响【目的】探讨在甲状腺功能亢进患者中不同甲状腺功能状况对BAT及其他器官糖代谢的影响。【方法】收集10例初发、未经任何治疗的Graves病甲亢患者,给予甲巯咪唑正规治疗。在治疗前和经甲巯咪唑治疗甲状腺功能恢复正常后,分别利用18F-FDG PET-CT检查确定其BAT及肌肉的糖代谢水平。同时收集48例PET-CT检查时发现BAT摄取阳性的健康体检者,在其检查同一天,收集48例BAT阴性对照者,分别测定入选者的甲状腺激素水平。【结果】治疗前,所有甲亢患者均无活性BAT显影,全身骨骼肌呈对称性FDG高摄取；而在治疗至甲状腺功能正常后,有一例女性患者出现阳性BAT摄取,所有患者的骨骼肌标准摄取值(Standard uptake value, SUV)值较治疗前明显下降(P≤0.001)。48例BAT摄取阳性体检者的游离三碘甲腺原氨酸(Free triiodothyronine,FT3)(P=0.003)和游离甲状腺素(Free thyroxine, FT4) (P<0.001)水平明显低于阴性对照者。【结论】甲状腺激素水平升高并未增加成人BAT活性,却明显提高了骨骼肌的糖代谢,提示骨骼肌强制性产热增加可能抑制了BAT的调节性产热。第三部分中国成人棕色脂肪活性与脑代谢的关系研究【目的】观察保暖干预前后BAT活性与脑代谢的关系,对BAT和大脑之间的神经反馈调节进行初步的探索和评价。【方法】收集15例BAT显影阳性的体检者,并按1∶2的比例收集30例性别、年龄、BMI、空腹血糖相匹配的BAT阴性体检者作为对照组。利用18F-FDG PET-CT检查比较两组的脑代谢水平。对BAT显影阳性者采取保暖措施后再次行PET-CT检查,并比较保暖前后BAT阳性者的脑代谢变化情况及保暖后两组的脑代谢差异。【结果】与对照组相比,BAT显影阳性组的顶下小叶、后扣带回和直回的代谢水平较低(P<0.01),而楔前叶代谢水平较高(P<0.01)。保暖后所有阳性者PET图像上的活性BAT摄取均消失。与保暖后的脑代谢相比,BAT阳性状态下的顶叶、额叶、小脑山顶、脑岛和扣带回代谢水平较低(P<0.05),而颞叶、海马旁回和后扣带回代谢水平较高(P<0.05)。保暖后,BAT阳性组的局部脑代谢水平与阴性对照组相比仍有统计学差异。阳性组的颞叶和边缘系统的代谢水平较低(P<0.01),而顶叶和楔叶的代谢水平较高(P<0.01)。【结论】BAT的活性与特定区域的脑代谢水平有关,保暖干预可引起部分脑区的代谢改变,进而影响BAT的产热活性。更多还原

【Abstract】 Obesity has become a serious threat in public health worldwide. Substantial epidemiologic evidence indicates that obesity is associated with hypertension, coronary artery disease, cerebrovascular accident, type 2 diabetes, dyslipidemia and cancers. Recent studies have shown active brown adipose tissue (aBAT) is present in adults and may play important roles in regulating energy homeostasis. This may be a potential target for the therapy of obesity and related metabolic disturbance.Very little is known about the prevalence of aBAT in Chinese adults. Almost all human cohort studies were done in patients for cancer surveillance and thus may not represent healthy subjects. And all studies just analyzed baseline characteristics such as sex, age, body mass index (BMI), history of cancer and fasting plasma gluscose (FPG), but the potential factors such as smoking, drinking, exercise and thyroid diseases, which are related to norepinephrine and thyroid hormone secretion, haven’t been included. The relationship between BAT activity, thyroid function and brain metabolism in adults are unclear. So we observed the characteristics of distinct adult cohorts with different BAT activities and thyroid functions, and explored the aBAT related factors and its central regulation mechanism. Our results may contribute to the foundation of future research in this area.Part I The Prevalence and Related Factors of Active Brown Adipose Tissue in Chinese AdultsObjective:To evaluate the difference between subjects for cancer surveillance and subjects for medical check-up, and determined the impact of life style and other parameters on aBAT.Methods:We analyzed 31,088 subjects who performed fluorine-18-fluorodeoxyglucose positron-emission tomography and computed tomography (18F-FDG PET-CT) from July 1,2006 to June 30,2010 at Huashan hospital and examined the characteristics of subjects with aBAT. Results:Active BAT predominantly exists from anterior neck to the thorax, and was seen in 410 of the 31,088 subjects (1.32%), which is lower than previous finding (5.37%). Among cancer surveillance patients, aBAT was found in 146 of 14,389 (1.01%), while it was 264 of 16,699 (1.58%, p<0.05) in medical check-up group. The prevalence of aBAT was higher in women (2.36%[273 of 11570]) than in men (0.70%[137 of 19518], P<0.0001). In both groups, the prevalence of aBAT is higher in women than men (1.59% vs 0.61%,3.16% vs 0.77%, P<0.0001, respectively). In univariate analyses of cancer surveillance group, aBAT was most frequently detected in women (P=0.0005), patients in the bottom third for age (<39.7 years, P=0.0077), the least obese patients (P<0.0001), and those who had never smoked, less drinking, moderate exercise and no fatty liver (P<0.0001, P=0.0015, P=0.0309 and P=0.0003, respectively). The univariate analyses of medical check-up group showed the same results except for exercise (P=0.1937). In age- and sex- adjusted multivariate analyses, BMI, smoking and exercise in the cancer surveillance group remained significant. BMI, smoking and thyroid hypermetabolism in medical check-up group remained significant.Conclusion:In Chinese adults, the prevalence of aBAT is 1.32% and cancer patients have lower prevalence than non-cancer subjects. It is correlated with BMI, smoking, exercise and thyroid diseases besides sex, age and temperature, suggesting the potential role in adult metabolism.PartⅡThe Effects of Thyroid Hormones on Glucose Metabolism of Brown Adipose Tissue and Muscle in Chinese adult humansObjective:The objective of this study was to investigate, for the first time, the effects of thyroid hormones on glucose metabolism of BAT and other organs in Hyperthyroidism.Methods:Ten Graves’disease-caused hyperthyroid patients who were newly diagnosed and untreated were included at our institution. Putative brown-adipose-tissue activity was determined by the integrated 18F-FDG PET-CT. All hyperthyroid patients treated with Methimazole were followed up when the symptoms had disappeared and the thyroid hormone levels were back to normal range within mean seventy-seven days. One of them was withdrawn because of drug allergy. Meanwhile, we studied a group of forty-eight BAT-positive healthy subjects by PET-CT scan, and forty-eight BAT-negative controls on the same scan day.Results:No hyperthyroid patient had active brown adipose tissue identified by PET-CT, except one showed active BAT after anti-thyroid therapy. The free triiodothyronine (FT3)(P=0.003) and free thyroxine (FT4)(P<0.001) were significantly lower in 48 BAT-positive subjects than BAT-negative subjects. All hyperthyroid patients showed symmetrically increased uptake of FDG in skeletal muscles before medical treatment. The standardized uptake value (SUV) was substantially decreased after treatment (P(?)0.001).Conclusion:The higher than normal circulating thyroid hormone levels increased the uptake of FDG in skeletal muscles significantly, but not in BAT, suggesting the increased obligatory thermogenesis of muscles may limit BAT activity in adult humans.PartⅢStudy on the Relationship between Brown Adipose Tissue Activity and Brain Metabolism in Chinese AdultsObjective:To observe the relationship between BAT activity and brain function before and after warm exposure, and assess the feedback regulation between BAT and brain.Methods:Relative regional cerebral glucose metabolism was compared between 15 healthy subjects with activated BAT and 30 healthy controls without activated BAT using brain fluorodeoxyglucose PET scan. A follow-up PET scan was performed to assess metabolic changes of the brain when BAT was disappeared by warm exposure.Results:Compared to controls, BAT-positive subjects exhibited lower activity in the inferior parietal lobule, limbic system and frontal lobe, and higher activity in the precuneus before warm exposure. Compared with the BAT elimination status, subjects with activated BAT showed a decreased metabolism in the parietal lobe, frontal lobe, culmen, cingulated gyrus and sub-lobar; and an increased metabolism in the temporal lobe, parahippocampal and posterior cingulate. Compared to controls, BAT-positive subjects with BAT elimination had significant hypometabolic areas in the temporal lobe and limbic lobe, and hypermetabolic areas in the parietal lobe and cuneus.Conclusion:The differences of regional cerebral glucose metabolism are related to BAT activities in BAT-positive subjects, and some of them can be changed following warm exposure. Brain responses are active in modulating metabolic function of the BAT activity.更多还原