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通讯作者:

王晓东,E-mail:drwangxd@vip.163.com

中图分类号:R581

文献标识码:A

文章编号:1007-4368(2022)05-679-05

DOI:10.7655/NYDXBNS20220512

参考文献 1
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KAISANLAHTI A,GLUMOFF T.Browning of white fat:agents and implications for beige adipose tissue to type 2 diabetes[J].J Physiol Biochem,2019,75(1):1-10
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WANG W S,SEALE P.Control of brown and beige fat de⁃ velopment[J].Nat Rev Mol Cell Biol,2016,17(11):691-702
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RABIEE A.Beige fat maintenance;toward a sustained metabolic health[J].Front Endocrinol(Lausanne),2020,11:634
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PHILLIPS K J.Beige fat,adaptive thermogenesis,and its regulation by exercise and thyroid hormone[J].Biology(Basel),2019,8(3):57
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MULLUR R,LIU Y Y,BRENT G A.Thyroid hormone reg⁃ ulation of metabolism[J].Physiol Rev,2014,94(2):355-82
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LIU G,LIANG L,BRAY G A,et al.Thyroid hormones and changes in body weight and metabolic parameters in response to weight loss diets:the POUNDS LOST trial [J].Int J Obes(Lond),2017,41(6):878-886
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参考文献 15
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参考文献 17
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参考文献 18
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参考文献 19
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参考文献 20
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参考文献 21
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参考文献 22
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参考文献 23
CHRISTOFFOLETE M A,LINARDI C C G,DE JESUS L,et al.Mice with targeted disruption of the Dio2 gene have cold ⁃induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis[J].Diabetes,2004,53(3):577-584
参考文献 24
PAULA B S,FRANCEMILSON G S,MARIA T N.Post⁃ transcriptional actions of triiodothyronine on TSHB ex⁃ pression in TαT1 cells:new insights into molecular mech⁃ anisms of negative feedback[J].Mol Cell Endocrinol,2018,478:45-52
参考文献 25
JOSÉ MARÍA M N,LAURA L P,MÒNICA S,et al.Adi⁃ pose TSHB in humans and serum tsh in hypothyroid rats inform about cellular senescence[J].Cell Physiol Bio⁃ chem,2018,51(1):142-153
参考文献 26
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参考文献 27
LIANG J,JIA Y,YAN H j,et al.Prdm16⁃mediated brown⁃ ing is involved in resistance to diet⁃induced and monoso⁃ dium glutamate⁃induced obesity[J].Diabetes Metab Syn⁃ dr Obes,2021,14:4351-4360
目录contents

    摘要

    目的:研究甲状腺激素合成和代谢相关基因表达与内脏脂肪米色化的关系。方法:收集甲状腺功能正常的正常体重和肥胖者的内脏脂肪组织,荧光实时定量PCR检测甲状腺激素合成和代谢相关基因、内脏脂肪米色化功能蛋白和转录因子的 mRNA 表达,并进行相关性分析。结果:肥胖者内脏脂肪组织甲状腺激素转运体包括溶质载体家族 16 成员 2 和成员 10 (SLC16A2、SLC16A10)、溶质载体有机阴离子转运体家族成员1C1(SLCO1C1)、促甲状腺激素β亚基(TSHB)和脱碘酶2(iodo⁃ thyronine deiodinase 2,DIO2)的mRNA表达均下降,其中SLC16A2、TSHB和DIO2差异有统计学意义。在校正年龄、性别、体重指数和FT3后内脏脂肪米色化功能蛋白UCP1及标志转录因子PR结构域家族成员16(PR domain⁃containing 16,PRDM16)的表达与上述基因表达呈正相关。结论:肥胖者内脏脂肪米色化功能下降与甲状腺激素合成和代谢密切相关。

    Abstract

    Objective:This study aims to study the relationship between thyroid hormone synthesis and metabolism ⁃ related gene expression and browning of visceral fat. Methods:The visceral fat tissues of normal weight and obese persons with normal thyroid function were collected,and the mRNA expression of genes related to thyroid hormone synthesis and metabolism,visceral fat beige functional protein and transcription factors were detected by fluorescence real⁃time quantitative PCR,then the correlation analysis was performed. Results:The mRNA expression of thyroid hormone transporters included solute carrier family 16 members 2 and 10 (SLC16A2,SLC16A10),solute carrier organic anion transporter family member 1C1(SLCO1C1)thyroid stimulating hormone β subunit(TSHB)and iodothyronine deiodinase 2(DIO2)decreased significantly in the visceral adipose tissue of obese people. There were significant differences in SLC16A2,TSHB and DIO2 between two groups The expression of visceral fat beige functional protein UCP1 and marker transcription factor PR domain⁃containing 16(PR domain⁃containing 16,PRDM16)are positively correlated with the expression of the above genes after adjusted by age,gender,body mass indexand FT3. Conclusion:Decreased beige function of visceral fat in obese people is closely related to thyroid hormone synthesis and metabolism.

  • 随着肥胖人数逐年增加,与肥胖相关的2型糖尿病、冠心病、脑卒中、肿瘤等疾病的发病率也显著升高,带来了沉重的社会经济负担[1-2]。能量摄入增加、消耗减少导致的脂肪组织蓄积是肥胖产生的主要原因。与皮下脂肪相比,内脏脂肪(viscer aladipose tissue,VAT)与血脂异常、胰岛素抵抗、冠状动脉粥样硬化等的发生发展关系更密切,危害更大[3]。已有研究发现,人体内不仅存在储存能量的白色脂肪 (white adipose tissue,WAT),还具有消耗能量的棕色脂肪。在成人体内发现的棕色脂肪可能主要由米色脂肪构成。大部分米色脂肪由具米色化功能的白色前脂肪细胞分化而来,也可以由白色脂肪细胞直接转化而来[4-6]。米色脂肪含有丰富的解偶联蛋白1(uncoupling protein 1,UCP1),通过解偶联线粒体氧化磷酸化,使多余的能量以热量形式散发,从而减少脂肪蓄积[5-6]

  • 甲状腺激素不仅影响生物的生长、发育和新陈代谢,在脂肪组织的发育、增殖、分化及代谢等方面也起着重要调节作用[7]。而甲状腺激素要在机体中发挥作用依赖于包括血循环中甲状腺激素水平、甲状腺激素转运体、脱碘酶、甲状腺激素受体在内的甲状腺激素合成和代谢系统[8]。研究早已证实促甲状腺激素(thyroid⁃stimulating hormone,TSH)水平与体重指数(body mass index,BMI)成正相关,而甲状腺激素水平降低导致脂肪蓄积[9-11]。但是,目前尚无在甲状腺功能正常情况下,甲状腺激素合成和代谢相关基因与内脏脂肪米色化功能关系的研究。本研究以甲状腺功能正常的肥胖人群为研究对象,探讨了甲状腺激素合成和代谢相关基因表达与内脏脂肪米色化的关系。

  • 1 对象和方法

  • 1.1 对象

  • 收集甲状腺功能正常[正常范围为游离三碘甲状腺原氨酸(FT)33.10~6.80pmol/L;游离甲状腺素(FT4)12.0~22.0pmol/L;TSH 0.27~4.20mU/L] 的减重代谢外科及胆道手术患者的大网膜脂肪组织共28例,每例组织量在1~2g。排除标准:既往有甲状腺疾病史;严重肝肾功能异常;患者入院前1个月有其他手术史以及服用影响脂肪功能的药物,如糖皮质激素、噻唑烷二酮类。术前收集患者基本资料包括性别、年龄、既往疾病史、服药情况。测量身高、体重、血压、腰臀围。空腹抽取静脉血,检测甲状腺功能、肝肾功能、血脂、血糖、糖化血红蛋白。本研究经本院伦理委员会批准,所有患者知情同意。

  • 1.2 方法

  • 1.2.1 组织总RNA提取和cDNA逆转录

  • 从手术室收取大网膜脂肪组织后立即放入液氮速冻,并转移至实验室-80℃冰箱保存。提取组织总RNA时,取出组织,加入300 μL TRIzol® (Cat No.15596018,Thermo Fisher Scientific公司,美国),匀浆机充分研磨组织(冰上操作),按试剂盒[Prime⁃ Script RT Master Mix(Perfect Real Time),Cat No.RR036A,TAKRA Bio公司,日本]方法进行组织总RNA抽提及cDNA逆转录。

  • 1.2.2 荧光实时定量PCR

  • 以上述组织cDNA为模板,用相关引物进行PCR扩增。定量PCR总反应体系为10 μL,反应条件:95℃预变性10min,94℃变性30s,60℃退火30s, 72℃延伸40s,80℃读板5s,40个循环,72℃~94℃,每升高0.5℃读1次作出熔解曲线。以GAPDH基因作为内参照,对目的基因的表达量进行分析。本研究所使用的引物序列详见表1。

  • 1.3 统计学方法

  • 计数资料采用例数表示,计量数据以均数±标准差(x-±s)表示,运用IBM SPSS 23.0软件和Graph⁃ pad 8.0软件进行数据统计分析和绘图。计数变量的比较采用卡方检验,连续变量组间比较采用 t 检验,相关性分析采用偏相关分析。P< 0.05为差异有统计学意义。

  • 表1 荧光实时定量PCR引物序列

  • Table1 Primers for realtime PCR

  • 2 结果

  • 2.1 正常体重和肥胖者的临床特征

  • 正常体重组平均BMI 23.97kg/m2,腰臀比0.91,肥胖组BMI 34.66kg/m2,腰臀比0.98,差异均有统计学意义(P< 0.01)。与正常体重组比较,肥胖组糖化血红蛋白、空腹血糖、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯水平均无明显差异;肥胖组空腹胰岛素水平高于正常体重组 (P=0.033)。所有患者甲状腺功能均在正常范围内, FT4、TSH水平在正常体重和肥胖者之间差异无统计学意义,肥胖患者FT3水平高于正常体重者(P=0.013,表2)。

  • 2.2 正常体重和肥胖者甲状腺激素合成和代谢相关基因表达差异

  • 为了研究甲状腺激素合成和代谢相关基因在甲状腺功能正常的正常体重和肥胖患者中表达情况,利用实时定量PCR检测了相关基因的mRNA表达。结果显示,甲状腺激素转运体包括溶质载体家族16成员2和成员10(SLC16A2,SLC16A10)、溶质载体有机阴离子转运体家族成员1C1(SLCO1C1)的表达在肥胖者的内脏脂肪均下降,其中SLC16A2差异有统计学意义。促甲状腺激素β亚基(TSHB)和脱碘酶2(iodothyronine deiodinase2,DIO2)的mRNA表达在肥胖组也下降(图1)。还对DIO1、DIO3、甲状腺激素α受体(THRα)、β受体(THRβ)的表达进行了检测,由于部分正常体重组内脏脂肪组织上述基因表达量低,定量PCR未能检测。以上结果表明肥胖者内脏脂肪组织中甲状腺激素合成和代谢相关基因表达较正常体重下降,导致甲状腺激素对肥胖内脏脂肪的受体后调控异常。

  • 表2 正常体重组和肥胖组临床特征比较

  • Table2 Comparison of clinical characteristics between normal weight group and obesity group

  • 2.3 甲状腺激素合成和代谢相关基因与内脏脂肪米色化的相关性

  • 已有研究证实,肥胖者内脏脂肪米色化程度远低于体重正常者。为了明确甲状腺激素合成和代谢相关基因表达变化与内脏脂肪米色化的相关性,检测了内脏脂肪米色化功能蛋白UCP1及标志转录因子PR结构域家族成员16(PR domain⁃containing16,PRDM16)的表达,并与甲状腺激素合成和代谢基因进行相关性分析。校正年龄、性别、BMI和FT3后, UCP1与SLC16A2、SLC16A10、TSHB、DIO2分别呈正相关;PRDM16与SLCO1C1、SLC16A2、SLC16A10、 TSHB、DIO2均呈正相关(表3)。说明肥胖者内脏脂肪米色化功能下降与甲状腺激素受体后的调控异常密切相关。

  • 3 讨论

  • 近年来,随着FDG⁃PET/CT的发展,研究发现成年人拥有可诱导的米色脂肪细胞[12-13]。米色脂肪功能的调控因素研究较多,包括寒冷刺激、体重变化、甲状腺功能等。研究表明,米色化功能与BMI成反比[14];随着体重的减轻,米色脂肪活性亦可增加。肥胖患者通过可调胃袋减重手术,1年后就可观测到米色脂肪活性增加[15]。早已证实甲状腺激素分泌过多显著增加米色脂肪功能[16-17];而经过药物治疗,随着FT3水平的降低,米色脂肪活性也随之下降[18]。甲状腺癌术后患者,激素补充治疗后,亚临床甲亢状态下米色脂肪活性明显增加[19]。在甲状腺功能减退小鼠中,尽管脂肪米色化基因的表达增加,但代谢活性仍是降低的[20]。在正常甲状腺状态下,甲状腺激素合成和代谢对米色脂肪功能的影响以及对肥胖者脂肪米色化功能调控至今不清楚。

  • 图1 甲状腺激素合成和代谢相关基因表达

  • Fig.1 Expression of genes related to thyroid hormone anabolism

  • 表3 校正年龄、性别、BMI、FT3后内脏脂肪米色化与甲状腺功能指标的相关性

  • Table3 Correlation between visceral fat browning and thyroid function indexes adjusted by age,gender,BMI and FT3

  • 甲状腺激素合成和代谢系统中,甲状腺激素通过特定的转运体SLCO1C1、SLC16A2、SLC16A10等从血液进入细胞。SLC16A2的缺乏可能导致甲状腺毒症迹象,包括体重减轻、肌肉萎缩及血清总三碘甲状腺原氨酸(T3)的升高;而SLCO1C1缺乏会表现出对寒冷的不耐受[21]。DIO2能够将总甲状腺素(T4)转换成更具有生物活性的T3。研究表明, DIO2在前脂肪细胞及米色脂肪细胞中大量表达[22]。 DIO2的缺失可导致米色脂肪功能异常,小鼠无法耐受寒冷[23]。T3可以在转录后水平快速降低TSHB的表达[23]。近期有研究提出TSHB表达可以延缓脂肪细胞衰老,增强线粒体功能[25]。本研究发现肥胖者内脏脂肪组织中SLCO1C1、SLC16A2、SLC16A10、 TSHB和DIO2的表达均明显低于正常体重组,提示在甲状腺功能正常人群,甲状腺激素受体后调节可能对内脏脂肪米色化功能起重要作用。

  • 目前认为UCP1是米色脂肪产热的关键介质,而PRDM16是PR结构域家族中的锌指转录因子,不仅参与白色脂肪的米色化,还能极强地诱导米色脂肪产热和消耗能量的功能[26-27]。本研究对UCP1、 PRDM16与甲状腺激素合成和代谢相关基因表达之间进行了相关性分析,结果显示,在甲状腺功能正常者,校正了年龄、性别、BMI和FT3后,UCP1和PRDM16的表达仍与内脏脂肪组织中甲状腺激素转运(SLC16A2,SLC16A10、SLCO1C1)、TSHB和DIO2的mRNA表达呈正相关。进一步说明内脏脂肪米色化功能的变化可能与甲状腺激素受体后调控密切相关。

  • 综上所述,甲状腺激素合成和代谢对内脏脂肪的米色化功能调控至关重要,且可能是通过受体后的调节来实现。但由于组织标本量受限,本研究无法进一步进行相关基因蛋白水平的测定,甚至离体实验进行因果关系验证,并且总例数也较少,存在一定局限性,具体机制还需进一步研究。

  • 参考文献

    • [1] CABALLERO B.Humans against obesity:who will win?[J].Adv Nutr,2019,10(suppl 1):S4-S9

    • [2] AFSHIN A,FOROUZANFAR M H,REITSMA M B,et al.Health effects of overweight and obesity in 195 countries over 25 years[J].N Engl J Med,2017,377(1):13-27

    • [3] JEMTEL T H L,SAMSON R,MILLIGAN G,et al.Viscer⁃ al adipose tissue accumulation and residual cardiovascu⁃ lar risk[J].Curr Hypertens Rep,2018,20(9):77

    • [4] KAISANLAHTI A,GLUMOFF T.Browning of white fat:agents and implications for beige adipose tissue to type 2 diabetes[J].J Physiol Biochem,2019,75(1):1-10

    • [5] WANG W S,SEALE P.Control of brown and beige fat de⁃ velopment[J].Nat Rev Mol Cell Biol,2016,17(11):691-702

    • [6] RABIEE A.Beige fat maintenance;toward a sustained metabolic health[J].Front Endocrinol(Lausanne),2020,11:634

    • [7] PHILLIPS K J.Beige fat,adaptive thermogenesis,and its regulation by exercise and thyroid hormone[J].Biology(Basel),2019,8(3):57

    • [8] MULLUR R,LIU Y Y,BRENT G A.Thyroid hormone reg⁃ ulation of metabolism[J].Physiol Rev,2014,94(2):355-82

    • [9] LIU G,LIANG L,BRAY G A,et al.Thyroid hormones and changes in body weight and metabolic parameters in response to weight loss diets:the POUNDS LOST trial [J].Int J Obes(Lond),2017,41(6):878-886

    • [10] PEKGOR S,DURAN C,KUTLU R,et al.Visceral adipos⁃ ity index levels in patients with hypothyroidism[J].J Natl Med Assoc,2018,110(6):606-613

    • [11] MAVROMATI M,JORNAYVAZ F R.Hypothyroidism⁃as⁃ sociated dyslipidemia:potential molecular mechanisms leading to NAFLD[J].Int J Mol Sci,2021,22(23):12797

    • [12] CHEN K Y,CYPESS A M,LAUGHLIN M R,et al.Brown adipose reporting criteria in imaging studies(BARCIST 1.0):recommendations for standardized FDG⁃PET/CT ex⁃ periments in humans[J].Cell Metab,2016,24(2):210-222

    • [13] LEITNER B P,HUANG S,BRYCHTA R J,et al.Map⁃ ping of human brown adipose tissue in lean and obese young men[J].Proc Natl Acad Sci U S A,2017,114(32):8649-8654

    • [14] YU J,LVY F,DI W J,et al.MiR ⁃ 27b ⁃3p regulation in browning of human visceral adipose related to central obe⁃ sity[J].Obesity(Silver Spring),2018,26(2):387-396

    • [15] VIJGEN G H E J,BOUVY N D,TEULEG J J,et al.In⁃ crease in brown adipose tissue activity after weight loss in morbidly obese subjects[J].J Clin Endocrinol Metab,2012,97(7):E1229-1233

    • [16] LAHESMAA M,ORAVA J,CAMILLA S J,et al.Hyper⁃ thyroidism increases brown fat metabolism in humans[J].J Clin Endocrinol Metab,2014,99(1):E28-35

    • [17] WEINER J,KRANZ M,NORA K,et al.Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice[J].Sci Rep,2016,6:38124

    • [18] SUN L J,GOH H J,VERMA S,et al.Metabolic effects of brown fat in transitioning from hyperthyroidism to euthy⁃ roidism[J].Eur J Endocrinol,2021,185(4):553-563

    • [19] BROEDERS E P M,VIJGEN G H E J,HAVEKES B,et al.Thyroid hormone activates brown adipose tissue and increases non⁃shivering thermogenesis ⁃ a cohort study in a group of thyroid carcinoma patients[J].PLoS One,2016,11(1):e0145049

    • [20] WEINER J,KRANZ M,KLÖTING N,et al.Thyroid hor⁃ mone status defines brown adipose tissue activity and browning of white adipose tissues in mice[J].Sci Rep,2016,6:38124

    • [21] GROENEWEG S,VAN GEEST F S,PEETERS R P,et al.Thyroid hormone transporters[J].Endocr Rev,2020,41(2):bnz008

    • [22] OBREGÓN M J,RUIZ DE OÑA C,HERNANDEZ A,et al.Thyroid hormones and 5′⁃deiodinase in rat brown adi⁃ pose tissue during fetal life[J].Am J Physiol,1989,257(5 Pt 1):E625-31

    • [23] CHRISTOFFOLETE M A,LINARDI C C G,DE JESUS L,et al.Mice with targeted disruption of the Dio2 gene have cold ⁃induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis[J].Diabetes,2004,53(3):577-584

    • [24] PAULA B S,FRANCEMILSON G S,MARIA T N.Post⁃ transcriptional actions of triiodothyronine on TSHB ex⁃ pression in TαT1 cells:new insights into molecular mech⁃ anisms of negative feedback[J].Mol Cell Endocrinol,2018,478:45-52

    • [25] JOSÉ MARÍA M N,LAURA L P,MÒNICA S,et al.Adi⁃ pose TSHB in humans and serum tsh in hypothyroid rats inform about cellular senescence[J].Cell Physiol Bio⁃ chem,2018,51(1):142-153

    • [26] FENZL A,KIEFER F W.Brown adipose tissue and ther⁃ mogenesis[J].Horm Mol Biol Clin Investig,2014,19(1):25-37

    • [27] LIANG J,JIA Y,YAN H j,et al.Prdm16⁃mediated brown⁃ ing is involved in resistance to diet⁃induced and monoso⁃ dium glutamate⁃induced obesity[J].Diabetes Metab Syn⁃ dr Obes,2021,14:4351-4360

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    • [11] MAVROMATI M,JORNAYVAZ F R.Hypothyroidism⁃as⁃ sociated dyslipidemia:potential molecular mechanisms leading to NAFLD[J].Int J Mol Sci,2021,22(23):12797

    • [12] CHEN K Y,CYPESS A M,LAUGHLIN M R,et al.Brown adipose reporting criteria in imaging studies(BARCIST 1.0):recommendations for standardized FDG⁃PET/CT ex⁃ periments in humans[J].Cell Metab,2016,24(2):210-222

    • [13] LEITNER B P,HUANG S,BRYCHTA R J,et al.Map⁃ ping of human brown adipose tissue in lean and obese young men[J].Proc Natl Acad Sci U S A,2017,114(32):8649-8654

    • [14] YU J,LVY F,DI W J,et al.MiR ⁃ 27b ⁃3p regulation in browning of human visceral adipose related to central obe⁃ sity[J].Obesity(Silver Spring),2018,26(2):387-396

    • [15] VIJGEN G H E J,BOUVY N D,TEULEG J J,et al.In⁃ crease in brown adipose tissue activity after weight loss in morbidly obese subjects[J].J Clin Endocrinol Metab,2012,97(7):E1229-1233

    • [16] LAHESMAA M,ORAVA J,CAMILLA S J,et al.Hyper⁃ thyroidism increases brown fat metabolism in humans[J].J Clin Endocrinol Metab,2014,99(1):E28-35

    • [17] WEINER J,KRANZ M,NORA K,et al.Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice[J].Sci Rep,2016,6:38124

    • [18] SUN L J,GOH H J,VERMA S,et al.Metabolic effects of brown fat in transitioning from hyperthyroidism to euthy⁃ roidism[J].Eur J Endocrinol,2021,185(4):553-563

    • [19] BROEDERS E P M,VIJGEN G H E J,HAVEKES B,et al.Thyroid hormone activates brown adipose tissue and increases non⁃shivering thermogenesis ⁃ a cohort study in a group of thyroid carcinoma patients[J].PLoS One,2016,11(1):e0145049

    • [20] WEINER J,KRANZ M,KLÖTING N,et al.Thyroid hor⁃ mone status defines brown adipose tissue activity and browning of white adipose tissues in mice[J].Sci Rep,2016,6:38124

    • [21] GROENEWEG S,VAN GEEST F S,PEETERS R P,et al.Thyroid hormone transporters[J].Endocr Rev,2020,41(2):bnz008

    • [22] OBREGÓN M J,RUIZ DE OÑA C,HERNANDEZ A,et al.Thyroid hormones and 5′⁃deiodinase in rat brown adi⁃ pose tissue during fetal life[J].Am J Physiol,1989,257(5 Pt 1):E625-31

    • [23] CHRISTOFFOLETE M A,LINARDI C C G,DE JESUS L,et al.Mice with targeted disruption of the Dio2 gene have cold ⁃induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis[J].Diabetes,2004,53(3):577-584

    • [24] PAULA B S,FRANCEMILSON G S,MARIA T N.Post⁃ transcriptional actions of triiodothyronine on TSHB ex⁃ pression in TαT1 cells:new insights into molecular mech⁃ anisms of negative feedback[J].Mol Cell Endocrinol,2018,478:45-52

    • [25] JOSÉ MARÍA M N,LAURA L P,MÒNICA S,et al.Adi⁃ pose TSHB in humans and serum tsh in hypothyroid rats inform about cellular senescence[J].Cell Physiol Bio⁃ chem,2018,51(1):142-153

    • [26] FENZL A,KIEFER F W.Brown adipose tissue and ther⁃ mogenesis[J].Horm Mol Biol Clin Investig,2014,19(1):25-37

    • [27] LIANG J,JIA Y,YAN H j,et al.Prdm16⁃mediated brown⁃ ing is involved in resistance to diet⁃induced and monoso⁃ dium glutamate⁃induced obesity[J].Diabetes Metab Syn⁃ dr Obes,2021,14:4351-4360