185

European Journal of Endocrinology -21-0366 Innovation, Agency for Science,Technology and Research (A*STAR), Singapore, 1 Melvin Khee Shing Leow Shaikh A K K Abdul Shakoor Brenda Su Ping Lim Yaligar Jadegoud Lijuan Sun euthyroidism transitioning fromhyperthyroidismto Metabolic effectsofbrownfatin the transitiontoeuthyroidismcorrelatedwithBATactivity. Conclusion: P P and Tscv.Significantchangesinserum-freetriiodothyronine (FT3)levelswererelatedtoBATstatus(interaction increased witheuthyroidism(72.3 to attaineuthyroidismwas28.6 Results: temperature (Tscv)quantifiedsBATactivity. sBAT mean/maximumstandardizeduptakevalue(SUVmean/max),MRsupraclavicularfatfraction(sFF)andmean with clinicalandbiochemicalparametersmeasuredduringhyperthyroidismrepeatedinearlyeuthyroidism. PET 18 (EE) measurementandsupraclavicularinfraredthermography(IRT)withinachambercalorimeter,aswell such ascarbimazole(CMZ)orthiamazole(TMZ)wasprescribedineverycase.Allunderwentenergyexpenditure Design: thyroid status. between supraclavicularbrownadiposetissue(sBAT)activityandphysiological/metabolicchangeswith in the transitionfromhyperthyroidismtoeuthyroidismarenotwellestablished,ourstudyinvestigatedrelationships Objective: Abstract School, Singapore of Singapore,and of Endocrinology,TanTockSengHospital(TTSH),Singapore, Singapore, Loo LinSchoolofMedicine, Singapore InstituteforClinicalSciences, value https://doi.org/ https://eje.bioscientifica.com F-fluorodeoxyglucose ( = Clinical Study 0.01) andrestingmetabolicrate(RMR)( ParticipantswithnewlydiagnosedGraves’diseasewererecruited.Athionamideantithyroiddrug(ATD) Twenty-one(16female/5male)participantsaged39.5 = 6 0.04). FT3concentrationathyperthyroidstatewaspositively associatedwithsBATPETSUVmean( Brownadiposetissue(BAT)controlsmetabolicratethroughthermogenesis.Asitsregulatoryfactorsduring Lee KongChianSchoolofMedicine,NanyangTechnologicalUniversity (NTU),Singapore, Hyperthyroidismdoesnotconsistentlyleadtoadetectable increaseinBATactivity.FT3reductionduring 10.1530/EJE 1 , Hui JenGoh 2 -21-0366 , Christiani JeyakumarHenry 6 , 5 7 Departments ofPhysiology&Medicine,NationalUniversity ofSingapore(NUS), , HuilingLiew 9 Cardiovascular andMetabolicDisordersProgram,Duke-NUSMedical 18 1 F-FDG) positron-emissiontomography/magneticresonance(PET/MR)imagingscanning, 1 , SanjayVerma 4 , 6 , 7 , 6 8 , , 7 9 , Wai HanHoi 2 ± Institute ofBioengineeringandBioimaging, L Sunandothers 2.3weeks.EightparticipantswereBAT-positivewhile13 wereBAT-negative.sFF ± 1.4%to76.8 6 Published by Bioscientifica Ltd. , 7 , Chee KianChew Printed inGreat Britain 2 P , PriyaGovindharajulu

© < 2021Theauthors 6 0.01). , 8 7 Yong LooLinSchool ofMedicine,National University , Siew PangChan ± 3 , 1.4%; 4 , S SendhilVelan P 6 ,

7 < , Timothy Peng LimQuek 0.01),butnochangeswereobservedinPETSUVmean 4 Brown fatandthyroidstatus Department ofBiochemistry,Yong ± 2.5yearscompletedthestudy.Theaverageduration 8 3 , Daniel EkChew Singapore InstituteofFoodandBiotechnology 3 , Suresh AnandSadananthan 1 , 2 , 5 , Pei ShanYeo 7 Department Attribution 4.0International License. This workislicensed under a 6 , 7 Downloaded fromBioscientifica.com at10/02/202103:29:12PM 6 , RinkooDalan , 7 6 , , 7 , YingshanLee [email protected] Email to M K Leow should be addressed Correspondence (2021) Endocrinology European Journalof 185 1 , NavinMichael 185 :4 6 , 553–563 , Creative Commons 7 and 6

, 7 , r

= 553 0.58,

–563 1 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com FDG uptake ofBAT lower inthe andsuprascapular neck replacement increased inhypothyroid with patients BAT Skarulis function. results regarding how status influences thyroid hormone published human studies have shown contradictory effects onBATclear. inhumansare not activity A few in lower mammals have been extensively studied, their among hypothyroid mice( ( mice demonstrating heightened accentuate glucose uptake inBAT, hyperthyroid with 17 andwhite (WAT)activation adiposetissue browning ( mitophagy pathway ( biogenesis andMTOR-mediatedvia mitochondrial towell BAT T3alsocontributes known that induction BAT absenceofT3( reduced inthe isgreatly uptake ( have more BAT, higher fattyacidoxidation, andglucose systemnervous andinducedBAT ( sympathetic or administration ofT3inrats the activated foressential BAT ( function isoform inBAT, TR BAT are well studied inrodent models.The T3receptor ( T3 ( and DIO Iodothyronine deiodinasetypes1and2(DIO1 utilization. control(T3), regulate energy processes metabolic that (T4) andits active metabolite 3,5,3 can have aprofound impact metabolic ( activity,metabolic even BAT asmallquantity offunctional obesityfor ( tackling ofBAT function makesthermogenic target it apotential obesity for its lipidandglucose-lowering effects ( target beimplicated to combat thus asatherapeutical glucose substrate.as a metabolic also utilizes BAT might Activated BAT oxidizes lipidsfor fuelpreferentially andit betweenrelationship BAT andobesity ( activity studies and clinical haveexperimental found an inverse significance inhumanadults remains unclear. Both expenditureof energy (EE).However, BAT's functional (NST)andisinvolvedthermogenesis regulation inthe excess form ofheatvianon-shivering stored inthe energy demonstrated inhumanadults( brown (BAT)Functional adipose tissue has been Introduction 18 10 Clinical Study , F-FDG) uptake inBATF-FDG) converse while the is true 18 ). The mechanisms of T3 and T4 in the regulation of regulation ofT3andT4inthe ). The mechanisms 9 Although thyroid hormones influencingBAT thyroid hormones Although function Two thyroxine forms ofthyroid hormones, chief ) that is essential for isessential BAT) that andactivity differentiation ). Rodent studies have proven thyroid hormones that 13 2 ) catalyze conversion the ofT4to its active form ). On the contrary, the thermogenic activity of contrary, activity ). Onthe thermogenic the β , isrequired andis for induction UCP1 8 ). Indeed,becauseofits high very 15 t al. et ). T3 is thus critical to BAT critical ). T3isthus 13 11 ( ). ). Systemic hyperthyroidism 19 ) reported levothyroxine) reported L Sunandothers 1 12 18 , F-fluorodeoxyglucose ). Hyperthyroid mice ). Hyperthyroid 2 , 2 ʹ 3 -triiodothyronine -triiodothyronine ). ). BAT dissipates 14 ). Ithasbeen 6 , 7 4 ). The , 18 16 5 F- ). ,

medical treatment in South East Asian patients with with East Asianpatients medical treatment inSouth from hyperthyroidism to euthyroidism following transition the occurduring that changes and metabolic 18 ofBATour study examined activity the by determined transitionfrom hyperthyroidism to euthyroidism,the humans andwhether BAT was altered activity during thyroid effect on BAT of status hormone the inadult existing literature.the To insight regarding gain further may have inconsistent ledtoin these results asreported participants research ofthe ethnicity scanning andthe are unclear. Differences inprotocols used for PET-CT induce BAT activity. The reasons for discrepancies these may thyroid hormones notconsistentlyof circulating which suggested highhyperthyroid patients levels that However, Zhang euthyroidglucose uptake comparedstate. the with havehyperthyroidism patients athree-fold higher BAT regions ( participation. informed from consentwas allsubjects obtained before ClinicalTrials.govwith (NCT03064542). Written code C/2015/00718 –TRIBUTEStudy) andregistered Group, Singapore Healthcare Board of National (Ethics procedures were approved Domain-Specific byReview the ofHelsinki,andall Declaration guidelines ofthe were excluded. of claustrophobia which hindered MRIscanning steroids) orBAT orhave (e.g.beta-blockers), ahistory which maymedication affect bodycomposition (e.g. allergic to (TMZ), taking carbimazole (CMZ), thiamazole Patients who were or contemplating pregnant pregnancy, test reflected (TFT)still frank biochemical hyperthyroidism. latest andiftheir thyroid function for amonth more than (ATD)(carbimazole/thiamazole)drugs were notinitiated receptor autoantibody. They were enrolled ifantithyroid TSH hyperthyroidism andapositive serum of primary evidence andclinical basedonlaboratory was diagnosed between October 2017 andJune2019. Graves’s disease ofalocalgeneral clinics hospitalwereoutpatient recruited Graves’diagnosed endocrine diseaseattending the betweenParticipants 21 and65years newly ofage with Study participants Subjects andmethods Graves’ disease. Brown fatandthyroidstatus F-FDG PET,F-FDG MR,andIRT, physiological together with The study was ethical conducted according to the 19 ). Lahesmaa et al. ( 21 Downloaded fromBioscientifica.com at10/02/202103:29:12PM ) did not detect active BAT in the t al. et ( 20 ) also reported that that ) alsoreported 185 :4 554 via freeaccess

European Journal of Endocrinology MRS, magneticresonancespectroscopy. dual-energy X-rayabsorptiometry; BMR,basalmetabolicrate;IRT,infraredthermography;PET, positron-emissiontomography; Study protocol.CMZ,carbimazole; TMZ,thiamazole;TFT,thyroidfunctiontest;Hx,PE,BIA,bioelectrical impedanceanalysis;DXA, Figure 1 andATDstandard medicalpractice dosestitrated against follow-up reviews at6–8weekly occurred asper intervals for hyperthyroidism. Clinic clinic control of their follow-uprequired with to endocrinology continue atthe BAT andabdominalwhite fatfor next the 1h. and followed by fusionPET-fat MRIscanningfor fraction radiolabeled glucose ( Center (CIRC). were The patients given ani.v. injection of for nextcalorimeter the 45min. area aboveand the collarboneinawhole-body room the stand focusing mounted onatripod neck onpatients’ camera (IRT)usingathermal infraredwith thermography rate measurement in awhole-body coupled calorimeter they metabolic underwent the measurements, finishing (DXA) which measures fat,lean,andbonemass.After X-rayevaluation usingdual-energy absorptiometry waist, andhipcircumference) andbody composition (i.e.measures ofbodyweight, height,anthropometry an overnight fast of8–10 underwent patients h.Allthe at 8:30 h after Research Centermorning (CNRC) in the hyperthyroid. still Visit 2for measurements baselineresearch while were they were for then scheduled CMZorTMZ.The patients with standard ATD therapy dosingregimen usingadecremental received they had consented to participate, participants the inascreening visit to evaluateparticipated eligibility. Once The study protocol isshown in Study protocol Clinical Study After completion of visit 2 procedures, the patients wereAfter completion patients ofvisit 2procedures, the ClinicalImagingResearch proceeded Then, to they the On study went ClinicalNutrition visit 2,patients to the 18 F-FDG) through the i.v. the through F-FDG) cannula L Sunandothers Fig. 1 . The patients . The patients Nutrition Research Center (CNRC).Nutrition The chambers WBC Clinical facility (WBC) locatedbody calorimeter atthe gaseousthrough exchanges whole- usingadual-chamber and after euthyroidism. achieving hyperthyroidism) atbaseline(during all study participants BodycompositionUSA). measurement was in performed densitometer, software version 8.21; Hologic,Waltham, (DXA) X-rayenergy fan-beam absorptiometry (QDR4500A, Fat mass,boneandleanmasswere measured by dual- Clinical measurements area, BAT,neck andabdominalwhite fatviaPET/MRscan. using DXA, rate, metabolic temperature patients’ inthe anthropometry, visit 3included during bodycomposition same fashionasstudy visit 2.The measurements performed study with visit 3inexactly the continued patients the achieved. This Subsequently, took upto about 6 months. teststhyroid andsymptoms function euthyroidism was till density lipoprotein (HDL)cholesterol, low-density ( The were details inourprevious reported publications supraclavicularAnterior temperature isdefinedas Tscv. measurements, ataconstant ambienttemperature of24 EE WBC sameroom asthe imaging was inthe performed were measured before Thermal andafter an intervention. in ourprevious publishedpaper( indetail dioxide The hasbeendescribed WBC production. (RQ) readouts basedonoxygen consumption andcarbon provide fatoxidation (FOX), EE, quotient andrespiratory are open-circuit air-tight and indirectcalorimeters Brown fatandthyroidstatus 23 , Resting energy expenditureResting energy (REE)was assessed 24 ). Fasting cholesterol, glucose,insulin,total high- Downloaded fromBioscientifica.com at10/02/202103:29:12PM https://eje.bioscientifica.com 22 ). REE, RQ, andFOX). REE, 185 :4 555 ° via freeaccess C. C. European Journal of Endocrinology https://eje.bioscientifica.com into BAT-positive and BAT-negative was 1.5 groups ( cut-off value ofsBAT PETSUV max subjectsfor categorizing sBAT segmented PET SUVmaxinthe region ( ofmeanMRFF, to computation prior PETSUVmean,and values was and bone marrow used to exclude muscle the radiologistclinical ( using ITK-SNAP guidanceofanexperienced close underthe sliceimages ofregisteredin multiple MRandPETimages manually basedonanatomical segmented information ISMRMfat-water Toolboxthe ( for was utilized fat-water using cut algorithm separation Agraph 2mmthickness. 96sliceswith mode, unipolar; 3 15 ms; TE’s, 1.1–8.61 ms ( was usedfor fat-water TR, (6 echoes) imaging with the slice thickness of view (FOV) (TR) time repetition 3D T1-weighted anatomical images were acquired using administered, 40minbefore imaging.High resolution for 60min.Intravenous injection of PET-MR system mMR,SiemensHealthcare) (Biograph referral laboratory. were University National by determined the Hospital renal, andliver parametersfree T3(FT3),TSH, function lipoprotein (LDL)cholesterol, triglyceride, free T4(FT4), by usingSPSSsoftware version 23(IBMSPSSInc.). analysis significant. statistically Statistical was performed stated. A unless otherwise for body weight. are presented Data as means betweento assessrelationships after variables adjusting were used correlations Spearman interactions. as their BAT status effects (BAT-positive andBAT-negative) as well status effects (hyperthyroidism andeuthyroidism),patient effects model was used to evaluatethe maineffects of Thebaseline andafter linearmixed- anintervention. to compare differencesthe parameters between the in Student’sassessed usingthe Differences between BAT-positive andBAT-negative were Statistical analysis (SSAT)superficial tissue depots( s.c.adipose level deep (DSAT) separated sets-based the algorithm and s.c.ATthe (VAT) andvisceral adiposetissue depotsand was usedto separate algorithm andquantify segmentation mMR, Siemens).Afully automated theoretic graph 2-point Dixon hybrid onthe MR-PET system (Biograph ° Clinical Study ; FOV, 384 MR images of abdominalfatwere acquired using All PETandMRscanswere by performed usingahybrid × = 288mm = 384 384

1 mm. A 3D multi-point gradient echo echo gradient 1 mm.A3Dmulti-point = 27 ×

5 ms, echo time (TE) time 5 ms,echo 288mm ). Alower of40%sFF threshold 2 ; matrix size192; matrix □ P TE -value t -test. Paired = 2 25 ; matrix size =384 size=384 ; matrix

~1.5 ms); flip angle (FA), L Sunandothers , ≤ 26 0.05 was considered 18 ). sBAT depotswere F-FDG (3mCi)was F-FDG t- = tests were used × 23

144; readout 2.46 ms,field , 24 31 , ± ). 28

29 × s.e.m. ). The 288, , 30 ). , to the euthyroid state.to There the werechanges nosignificant and FOXthe from decreased hyperthyroid significantly euthyroid state ( hyperthyroid statehigher compared inthe the with change inpercentageno significant bodyfat( mass ( hyperthyroidism to euthyroidism ( was a significant increase in body weight from euthyroidism states were in summarized hyperthyroidism andearly during participants total of andimagingcharacteristics Clinical, biochemistry required euthyroidism to was reach 28.6 completed study. the The average oftreatment duration were study. into recruited the Twenty-one participants Graves’ diagnosed recently with disease participants Thirty Clinical measurements Results (BAT-positive andBAT-negative subjects) to examine the and euthyroid state were shown in positive andaBAT-negative inhyperthyroid participant Representative images of PET, MR, and IRT from a BAT- BAT-positive andBAT-negativeparticipants Imaging andclinicalparametersbetween (72.3 in BAT euthyroid state hyperthyroid to the sFFfrom the at room temperature. There was asignificantincrease BAT Tscv mean from hyperthyroidism to euthyroidism changes inBATsignificant SUVmean,BAT SUVmax,and were shown in participants sBAT measured viaPET, activity MR,andIRTinallthe IRT imaging sBAT activityassessedusingPET,MR,and from hyperthyroidism toconcentrations euthyroidism. conjugated,significant decreases inbilirubin AST, andALT andalbuminlevelincreases increatinine ( hyperthyroidism to euthyroidism. There were significant changesSAT, in no significant VAT, and DSAT from triglyceride andNEFA levels. state ( the euthyroid the to from hyperthyroid significantly cholesterol, LDL-cholesterol, HDL-cholesterol increased glucose,insulinlevels, total in serum orHOMA-IR. Serum Brown fatandthyroidstatus The baseline RMR of the participants was significantly was significantly participants The baseline RMR of the We 21 separated the subjects based onBAT status There was asignificant increase inSSAT, but ± P P 1.4; 76.8

< < 0.01), andfatmass( 0.001).changes No significant were found in ± P 1.4, respectively;

< 0.001). RQ increased significantly Downloaded fromBioscientifica.com at10/02/202103:29:12PM P

= Table 2

0.04). However, was there P Fig. 2 P

<

< 185 0.01), aswell aslean 0.01). . There were no . :4 Table 1 ± P 2.3weeks. P

=

0.71). < 0.001), . There 556 via freeaccess

European Journal of Endocrinology LDL (mmol/L) Total cholesterol(mmol/L) HOMA-IR Fasting insulin(µU/mL) Fasting glucose(mmol/L) FOX RQ RMR (kcal/day) Lean mass(kg) Fat mass(kg) Body fat(%) Body weight(kg) acids; RMR,restingmetabolicrate;RQ,respiratoryquotient;s.c.AT,s.c.adiposetissue;SSAT,superficialSAT;VAT,visceraltissue. HDL, high-densitylipoprotein;HOMA-IR,homeostasismodelassessmentofinsulinresistance;LDL,low-densityNEFA,non-esterified fatty ALT, alanineaminotransferase;AST,aspartateDSAT,deepSAT;FOX,fatoxidationrate;FT3,freetriiodothyronine;FT4,thyroxine; ALT (U/L) AST (U/L) Bilirubin conjugated(µmol/L) Albumin (g/L) Creatinine (µmol/L) FT4 (pmol/L) FT3 (pmol/L) SSAT (cm DSAT (cm VAT (cm SAT (cm NEFA(mmol/L) Triglyceride (mmol/L) HDL (mmol/L) association with patients’ thyroid status patients’ ( with association Forinteraction. was cholesterol, total asignificant there was significant association BATfound with their or status thyroid status patients’ ( associated with thyroid status ( affected by BAT ( status compared BAT-negative with MR FFwas participants. level. BAT-positive had a higher Tscv participants mean affected only by BAT thyroid andnot status by hormone ( BAT with was asignificant association max, there status MR FFasperourprevious protocol ( according to nodetectable with a PET/MRSUVmax detectable with two those groups: were hyperthyroid state. Participants dividedintoin the haddetectable sBAT participants atroom temperaturethe status andBATpatients’ status effects ( BMI (kg/m model assessmentofinsulinresistancewascalculatedasfastingglucose Data arepresentedasmean Table 1 P P valuesrepresenttheStudent’s Clinical Study

=

0.008) but not patients’ thyroid but notstatus.patients’ Tscv0.008) mean was 3 3 ) ) 3 3 ) Characteristics oftotalparticipantsduringhyperthyroidismbeforetreatmentsandearlyeuthyroidismstate. 2 ) ) 18 P

F-FDG uptake andco-registered F-FDG with < 0.001). For was significantly RMR,this 18 ≥ F-FDG uptake (BAT-negative;F-FDG 1.5 (BAT-positive; P t

-test betweenhyperthyroidismandearlyeuthyroidism,phases. ± = S.E.M.BMIwascalculatedasbodyweight (kg)dividedbythesquare ofheight(m).Homeostasis

0.014) andalsoby patients’ L Sunandothers 18 F-FDG uptake with uptake with F-FDG 32 P Table 3 n

). For PETSUV < P

= 0.001) butno

<

8) and those 8) andthose 0.001) and ). Not all n

= Hyperthyroidism 1718.6 13) 31.8 22.9 54.7 0.08 0.82 33.8 19.5 34.7 55.6 21.7 41.0 28.6 40.2 51.9 29.9 10.5 22.9 0.7 1.4 1.4 2.6 4.6 1.1 5.4 4.4 3.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± after adjustingt for weight, euthyroid state butnotinthe hyperthyroid state andPETSUVmean( There was a positive between association FT3 level in related markers Relationship ofFT3andFT4BAT- status ( was a marginally BAT significant association found with ( interaction status ( patients’ the with correlation werestate which inturn affected by BAT status. For FT4, decreased fromconcentration hyperthyroid to euthyroid BAT status ( there werethere significant effectsstatus ( forpatients status effects ( status effects andmarginallypatients significant BAT LDL-cholesterol and triglyceride, were there significant BAT status ( Brown fatandthyroidstatus 4.2 2.9 5.9 0.1 0.2 0.1 0.2 0.2 0.1 0.7 0.1 0.01 0.01 87.7 1.6 1.6 1.8 2.6 6.0 2.4 0.4 0.6 3.3 3.0 0.9 1.8 0.9 × fastinginsulindividedby22.5. P

= 0.083). P P P

= P

=

= = 0.04), and interaction ( = 0.04),andinteraction 0.044), but not for their interaction. For butnotfor interaction. 0.044), their

0.015) were highly significant, whereas .8 and 0.08 1430.2 Euthyroidism 30.2 22.6 53.9 0.06 0.84 35.7 20.3 34.5 58.5 22.9 19.1 21.0 43.4 64.3 12.3 23.7 Downloaded fromBioscientifica.com at10/02/202103:29:12PM 0.6 1.2 1.7 3.3 5.6 1.2 6.1 4.5 2.5 5.5 P

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± = 3.9 3.0 5.5 0.1 0.2 0.1 0.2 0.3 0.2 0.8 0.1 0.004 0.01 65.2 1.8 1.7 1.8 2.9 1.1 2.0 1.0 0.3 0.5 4.6 1.3 0.3 1.7

0.06, respectively). For FT3, https://eje.bioscientifica.com 185 P

< :4 r 0.001) andtheir

= 0.58, P

= P < < < < < < < < < < < < < .4. FT3 0.04). n -values P 0.001 0.003 0.007 0.001 0.001 0.001 0.001 0.001 0.9 0.68 0.21 0.26 0.06 0.001 0.001 0.001 0.39 0.33 0.71 0.001 0.001 0.001 0.001 0.04 0.71 0.001 0.001

=

< P 21. 0.001),

= 557 0.01) via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com SUV, FF,andTscvareshownof thecorrespondingregionofinterest. drawn aroundsBATontheanatomical MRimages,PET,FF,andIRTmapsshowingthelocation ofsBAT.Thevalues(mean which colorscaleshowsvalues ofstandardizeduptakevalues(SUV),FF(in%),andTscv,respectively. Theregionsofinterest(ROI) 18 negative subject(B)athyperthyroidism (top)andeuthyroidismstage(bottom).(a)T1-weighted anatomicalMRimagesBAT,(b) Representative imageshighlightingsupraclavicularbrownadipose tissue(sBAT)fromaBAT-positivesubject(A)andBAT- Figure 2 P P ( was positively FT4inhyperthyroid state associated with P inhyperthyroid state ( FT3both associated with in euthyroid state ( ( supraclavicular temperature. MR, magneticresonance;SUV,standardizeduptakevalue;Tscv,anterior BAT, brownadiposetissue;FF,fatfraction;IRT,infraredthermography; early euthyroidismphases. Change Euthyroid Hyperthyroid BAT Tscvmean( Change Euthyroid Hyperthyroid BAT FF(%) Change Euthyroid Hyperthyroid BAT SUVmax(g/mL) Change Euthyroid Hyperthyroid BAT SUVmean(g/mL) patients. measured inthehyperthyroidandeuthyroidstate21 Table 2 P Table 4 r

valuesrepresenttheStudent’s F-FDG PET(c)thefatfraction(FF) map.(d)IRTmapwithcolorbarshowingthetemperature in = =

= = 0.12). FOX was positively FT3( associated with Clinical Study

0.001) andeuthyroid state ( 0.01), FT4 ( 0.57, ). FT3was positively Tscv associated with mean n Changes inPETBATSUV,MRFF,andIRTTscvmean P

=

= 21. Dataarepresentedasmean

0.01) butnotineuthyroid state ( r °

= C) 0.52, r

= –0.04 –0.01 Mean 0.55, 35.6 35.7 76.8 72.3 P 4.4 0.2 1.9 1.7 0.8 0.9

= t

0.02) in hyperthyroid state and -test betweenhyperthyroidismand ± ± ± ± ± ± ± ± ± ± ± ± ± P

0.1 0.1 0.7 1.4 1.4 0.3 0.2 0.2 0.1 0.1 0.1 0.1 s

. = e . m

0.01). RMRwas positively . r L Sunandothers

= 0.63, –1.02–0.07 34.5–36.7 63.9–86.5 60.6–83.2 –0.4–1.1 –2.8–2.8 1.1–10.4 0.3–4.4 0.8–4.3 0.1–1.5 0.4–1.9 35–36.3 Range P ±

=

s . .0) RMR 0.003). e . m . r r r P

= 0.69, = = < -values 0.69 0.01 0.52 0.93 0.36, 0.59, have extensively beendescribed literatures inthe ( hyperthyroidism to euthyroidism. to transition fromcorrelated BAT the during activity detectable BAT was significantly FT3reduction andthat had finding was asmall number of patients hyperthyroid on BAT Our key independent of cold stimulation. activity study,In ourcurrent we examined hyperthyroidism effects have effects metabolic onBAT development andfunction. involved Thyroid may ofEE. regulation hormones inthe BAT expenditureenergy (EE)andthermogenesis. is increased resting with inmetabolism changes multiple isahypermetabolic state leadingtoHyperthyroidism Discussion state ( FT3 ( body masswas decreased which suggested patients that to ATD hyperthyroidism, prior with patients therapy, lean fat aswas previously consistently reported ( inpercentage nochange bodymass, andleanwith accompanied by significantincreases inbody weight, fat becameeuthyroid. This was hyperthyroid participants our study, EEdecreased resting significantly when the homeostasis. In inenergy changes is associated with which increase BMR( hormones development ( homeostasisgrowth ofEEandBMRfor and benefit of the 34 Brown fatandthyroidstatus ). One of the main functions of thyroid hormone is the isthe ofthyroid hormone mainfunctions ). Oneofthe Thethyroid onbodycomposition effects of hormones r

Table 4 = 0.70, ). P

= 35

0.001), FT4( ). The thyroid glandsecretes thyroid Downloaded fromBioscientifica.com at10/02/202103:29:12PM ° C. ThePET,FF,andIRTmapsin r

= 0.52, 36 ). Thyroid dysfunction P 185

=

0.02) ineuthyroid :4 37 , ± 38

s 558 . d ). In . ) of 33 via freeaccess , European Journal of Endocrinology significant valuesareinbold. Significant correlationsbetweenvariables areshowninboldwithcorrespondingcoefficient(r)and FOX (g/min) RMR (kcal/day) Tscv mean( sFF (%) PET SUVmean(g/mL) correlations wereusedtoassesstherelationshipbetweenvariables afteradjustingforweight. Table 4 MR and/or IRT can as serve effectivethat non-ionizing BAT. Inourprevious study ( as safer alternatives for quantitative measures of serial, (IRT)haveinfrared thermography emerged more recently of imagingBAT. resonance (MR)imagingand Magnetic previous studythe ( were findingsof consistent study the participants with glucose,insulin,andcholesterol levelsincluding inour inconsistency.the parameters metabolic changes Other may have proportions gender andethnic to contributed women inSingapore. Perhaps slightly different the in fat-free massafter euthyroidism achieving inChinese changesignificant increase no in percentage body fat with protein However, catabolism. Chng kg) probablyand dueto adecrease inthermogenesis afatmassincrease (from 19.5than The ofincrease magnitude inleanbodymasswas greater achieved euthyroidism (from 33.8 significant increase inleanbodymass theyby ~2kg when food intake ( due to a decrease in lean body mass despite increased hyperthyroidism hadweightwith losspredominantly Statisticallysignificantvaluesareinbold. FT4 (pmol/L) FT3 (pmol/L) Triglyceride (mmol/L) LDL (mmol/L) Total cholesterol(mmol/L) RMR (kcal/day) Tscv mean( sFF (%) SUVmax (g/mL) interactions betweenpatients’statusandBATweretestedusinglinearmixed-effectsmodel. BAT-positive Table 3 Clinical Study 18 F-FDG PEThas beenregarded gold standard asthe F-FDG Correlations betweenFT3orFT4andimagingparameters,RMR, andFOXathyperthyroideuthyroidstate. Imaging andclinicalparametersofBATpositivenegativepatientsathyperthyroideuthyroidstate. ° ° C) C) n =8, BAT-negative 33 , 38 39 ). Our study participants hada ). Ourstudy participants ). 1839 BAT-positive 37.9 13.0 35.9 68.1 1.0 2.1 4.0 2.4 24 n =13. Dataarepresentedasmean ± ± ± ± ± ± ± ± ± ), we have demonstrated 0.59 (0.01) 0.69 (0.001) 0.20 (0.39) 0.32 (0.17) 0.58 (0.01) 4.6 1.7 0.1 0.2 0.3 171 0.1 1.5 0.3 L Sunandothers Hyperthyroid ± 1.6 to 35.7 FT3 et al. ± 1.6 to 20.3 1645 BAT-negative ( 25.0 35.5 74.9 8.9 1.6 2.9 5.0 1.3 39 Hyperthyroid ) reported a) reported ± ± ± ± ± ± ± ± ± 3.3 0.9 0.3 0.3 0.3 95 0.1 1.8 0.1 ± 1.8 kg). ± 1.7 1.7 − 0.52 (0.02 0.57 (0.01) 0.22 (0.35) 0.23 (0.33) 0.59 (0.01) 1494 BAT-positive 12.8 36.0 72.7 5.9 0.7 2.9 4.9 2.1 FT4 BAT activity without cold stimulation. WeBAT coldstimulation. without activity found that PET, MRFF, IRTTscv, to detect andwhole-body calorimetry study, Inourcurrent cold stimulation. we used alternatives to negative groups. cut-off value as the to define BAT-positive and BAT- studies ( and other BARCIST 1.0on the (BAT inImagingstudies) criteria cold exposure inourprevious study ( lessBATinduced significantly compared activity with study,in ourcurrent we found thyroid hormones the cut-off exposure,value isSUVmaxof2.0.However, the studies ( other differentgroups. Inourprevious research study ( off SUV value to define BAT-positivity in is also varying diverse. was rather activity more Until recently, cut- the using FDG/PET to The measure method BATparticipants. 18 21 early showed stage hyperthyroid patients detectable euthyroid levels We ofthyroid hormones. found 8of that restoration of the with BAT participants inallthe activity to euthyroid status which isconsistent adecrease of with only increased MRFFwas from significantly hyperthyroid ± ± ± ± ± ± ± ± ± Brown fatandthyroidstatus ± 1.7 0.6 0.1 0.3 0.4 151 0.1 1.1 0.4 F-FDG PET uptake which we definedasBAT-positiveF-FDG

s ) Euthyroid . e . m . Thepatients’statuseffects,BATand BAT-negative 1391 11.9 35.4 79.3 5.2 1.5 3.6 6.0 1.8 ± ± ± ± ± ± ± ± ± − 40 18 P valuesadjustedforbodyweight.Statistically 1.9 0.3 0.3 0.3 0.4 55 0.1 1.9 0.3 0.70 (0.001) 0.63 (0.003) 0.55 (0.01) 0.02 (0.93) 0.10 (0.67) F-FDG PETto evaluateF-FDG BAT after activity , 41 29 FT3 ) in healthy participants after cold ) inhealthy participants , Patients status 30 Downloaded fromBioscientifica.com at10/02/202103:29:12PM

< < < < < 0.907 ), we adopted SUVmaxof1.5 0.708 0.001 0.001 0.024 0.001 0.001 0.001 0.001 effects Euthyroid https://eje.bioscientifica.com P 32 185 values BAT status 0.083 0.06 0.077 0.340 0.037 0.044 0.006 0.014 0.008 effects ). Therefore, based :4 0.52 (0.02) 0.36 (0.12) 0.37 (0.11) 0.14 (0.55) 0.07 (0.78) FT4 Interaction n 0.094 0.845 0.838 0.353 0.265 0.897 0.283 0.015 0.04 18 n

32 =

F-FDG F-FDG = 21, 559 ) and 21. via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com in infantsandsmallmammals ( of fuelsubstrates expression ofUCP-1 andthe inBAT availability orsynergisticallyindependently to the change system nervous sympathetic and the either (SNS)act ( site offacultative thermogenesis BAT latter development beingamajor the andfunction, play role in animportant ofthermoregulation, mediators study BAT underdifferent conditions. More isneededto research explore different to approaches to study approach humanBAT. optimized acceptable, MRI( measurements with to betaken into accountwhen fat fraction performing FDG PET and IRT. However, volume effects need partial study BAT coldexposure without compared activity with ( tissue depot s.c.adipose lean mass, andsuperficial volume shown by calorimetry, as well as an increase in fatmass, accompanied byofRMRandfatoxidation as areduction BAT treatment. This was after drug antithyroid activity euthyroid state,to which suggested the in areduction hyperthyroid transitionedfrom the asthey participants BAT-positive andBAT-negative (asdefined by FDG-PET) study,current we found MRFFwas increased inboth that require coldexposure to detect BAT ( activation as tracers such useof dueto the detection PET-CT necessary status sensitivityfor may the lack BAT didnotrevealthat BAT inthyroid changes with activity diabetes ( by BAT hasbeenshown with inastudy onpatients selective impairment ofglucose butnotfattyaciduptake glucose( than fuel rather BAT activated that oxidizes predominant fatty acids as the [ as14(R,S)- such fattyacid-basedradiopharmaceuticals with FDG isnotasensitive indicator ofBAT compared activity MRFFhasalsobeenusedtostimulus. study BAT. Also, unlike ourpresent study which involved nocooling better suited to detect BAT post-cold exposure, activity ( previous report for most BAT imaging( BAT by as exploited activity PET and IRTmethodologies uptake andBAT temperature well correlate changes with EE canbemeasured ( forstimulus BAT and following an increase in activation, well coldexposure known most isby that potent farthe status, PETSUVmax,andIRTTscv Itis didnotchange. earlier reported experimental hyperthyroidism-induced earlier experimental reported 18 Table 1 Clinical Study F]-fluoro-6-thia-heptadecanoic acid( F]-fluoro-6-thia-heptadecanoic Thyroid hormones, long recognized as crucial Thyroid ascrucial longrecognized hormones, transitionfrom hyperthyroid to euthyroid the During ). Hence,MRFFmay beamore sensitive to method 43 ). Hence, all earlier published human studies 18 24 FTHA ( ). Hence, 41 30 ). Upon coldexposure, 43 45 ) which isconsistent our with 42 ). Notably, MRFFdoesnot 18 , 18 ). This is important sincea). This isimportant 46 F-FDG instead offattyacid F-FDG F-FDG PETandIRTmay be F-FDG ). There nowidely isstill L Sunandothers 47 47 ). Thyroid hormones ). Masini 18 FTHA), given 44 t al. et ). Inour 18 F-FDG F-FDG ( 18 48 F- ) effects onBAT euthyroid conditions. undernormal Expectedly, it isdifficult to examine thyroid hormone hyperthyroid state compared hypothyroid to the state. BATthe subclinical increased in significantly activity ( stimulation BAT thyroid with the relating were conducted usingcold ofBATregulation ( activation BAT,activated implying a role for in the thyroid hormone level receptors expressed nuclear in ofthyroid hormone Some adulthumanstudies alsodemonstrated ahigher BATsupported by elevated activation thyroid hormones. which glucose uptake compared healthy participants, with ( tenablenot ethically Minna inmost countries. ofthyrotoxicosisinduction for isoften research clinical activity. Similarstudies inhumansare limited asiatrogenic playedfunction by for thyroid hormones BAT and growth ofBATmodification in rats proved which the critical people important for thermoregulation ( forpeople important thermoregulation existence ofa physiological feedforward loopineuthyroid existencethe ofaBAT-thyroid axisanddemonstrated the investigation. we to established this, further Asacorollary andBAThormone inadulthumansevidentlyneeds between The relationship are being normalized. thyroid a decrease in BATinferring as thyroid hormones activity hyperthyroid to euthyroid status inevery subject, thereby byfat fraction MR FF in sBAT transition from the during We adipose tissue. the within detected anincrease inthe might bedependent onambientintracellular T3levels in asystematic review BAT that by detection forbeen initiated 3–4weeks. Santhanam had were after patients drugs recruited antithyroid these might have because SUVthreshold diminishedbelow the it ispossiblethat active BAT remaining 13 amongthe hyperthyroid patients, have inconsistency. to the contributed Regarding of lack the was notclearly may known andthis participant of each Graves’ disease.However, ofhyperthyroidism duration the are newly with diagnosed Ourparticipants participants. highersignificantly inBAT-positive relative to BAT-negative compared to BAT-negative IRTTscv participants. was also lowerFF was significantly inBAT-positive participants compared to BAT-negative Additionally, participants. MR higherwas significantly inBAT-positive participants detectable BAT activity. Inoursubjects, PETSUVmax However, had atleast 38%ofourhyperthyroid patients may increase hormone BAT notnecessarily activity. high thyroid and postulated abnormally circulating that did notfindactive BAT inany patients hyperthyroid Brown fatandthyroidstatus 20 ) reported hyperthyroid participants hadhigher BAT hyperthyroid participants ) reported Enigmatically, Zhang 50 , 51 18 F-FDG uptake at classical BAT uptake atclassical F-FDG depotsites ). Notably, Evie Downloaded fromBioscientifica.com at10/02/202103:29:12PM t al. et 49 ( ). Many previous studies 21 et al. ) reported that they they that ) reported 185 ( et al. 42 :4 52 ). ) reported that that ) reported ( 18 53 F-FDG PET F-FDG ) reported ) reported 560 t al. et via freeaccess

European Journal of Endocrinology duration of hyperthyroidism before participating inour ofhyperthyroidism beforeduration participating Hence the bydoctors. their drugs antithyroid prescribed they time were was differentthe dependingon participant dysfunction for ofthyroid hormone duration each the carbimazole/thiamazole, 1–4weeks ofinitiating a brief of butwithin first diagnosis hyperthyroidism upon the Thirdly,adipose tissue. were patients notrecruited asthe difficult tobe thesupraclavicular especially in excluded Very smallvessels, lymph nodes,andadjacent are muscles (e.g. from vessels) a voxel. within portions lipid tissue differentiate between intracellular water content andnon- as due effects,to such voxel MR FF cannot size limitations. FF isknown limited to besignificantly volume by partial The study MRI-basedstatic ofhyperthyroid patients. in this FF ismore sensitive indemonstrating BAT changes activity IRT was relatively limited compared to MRI. Secondly, MR level the ofBAT that ofdetection such via before andafter treatment were disparate notsufficiently what wethan have The comparable anticipated. effects 18 before the exposure participants was notappliedto the are BAT-positive ( higher beingfound who thyroid hormones amongthose probabilityBAT of increases the which inturn activation, results brown ingreater and adipocyte differentiation ahigher thyroid outputby thyroidthat hormone the sBATwith PETSUVmean.We have previously proposed ahyperthyroid state wasduring positively associated expectedly leadsto alower BAT activity. FT3concentration status andBAT inFT3 status for areduction FT3.Assuch, There was between a significant interaction the patients’ hyperthyroid andeuthyroid states. the inboth patients higher inBAT-positive compared patients to BAT-negative was significantly FT3concentration circulating that of supraclavicular BAT. study, Inourcurrent we alsofound biologically active T3may beinvolved development inthe ( negative participants higher inBAT-positive BAT- than healthy participants FT3levelwe that hadreported atbaseline was significantly which converts T4to active T3( amount oftypeII5’iodothyronine deiodinase(DIO ofUCP1.and up-regulation BAT anabundant contains ofbrown for recruitment adipocytes the of T3isnecessary exposure to during observed cold( ofbrownthat likedifferentiation adipocyte precursors, of BAT, may early induce avery proliferation and the lipidcontent in known modifications inducing the F-FDG PET/MRI andIRT.F-FDG BAT Hence,the islower activity Clinical Study The First, present study cold hassomelimitations. T3,besides that Some animalstudies concluded 55 ). 55 ). Junker 54 L Sunandothers 48 ). Inourprevious study, et al. ). High concentration ( 56 18 F-FDG PETand F-FDG ) reported that that ) reported 2 ) Research (A*STAR)awardedtoA/Prof.MelvinLeow. NMRC/CSA-INV/0003/2015) and the Agency for Science, Technology and Medical Research Council (NMRC) Clinician Scientist Award (grantID The study wassupported bytheSingaporeMinistryofHealth’sNational Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest activity. is an accompanyingeuthyroidism, there of BAT reduction With of coldstimulation. attainment or IRTwithout the compared toand whole-body calorimetry BATactivated which is better demonstrated using MR FF results level fallingbelow significance. the ofstatistical study was differentthis may have and to some contributed References The authorsthankthevolunteerswhoparticipatedinthistrial. providing the multi-echo Dixon prototype for the mMR Biograph system. The authorsthank Dr Stephan Kannengiesser, Siemens Healthcare for Acknowledgements the finalmanuscriptandapprovedforpublication. and criticallyreviewedthemanuscript.Allauthorscontributed to editing study, assisted in data interpretation,provided intellectual inputs, edited critically reviewed the final manuscript; M K S L conceived and designed the H H, TPE Q, C K C, DEK C, and R D recruited the patients, edited and inputs and criticallyreviewedthemanuscript;PSY,YL,BAS,W analyzed the data;CJH and S S Vdesigned the study, provided intellectual the manuscript;HJGandPconductedstudy;SKV,AS,NM L JSconducted the study,analyzed the data,interpretedresults,andwrote Author contributionstatement Brown fatandthyroidstatus 3 2 1 4 Pfannenberg C, Werner MK, Ripkens S, Stef I, Schmadl M, Deckert A, Cypess AM, Lehman S,Williams G, Tal I, Rodman D, Goldfine AB, Orava J,Virtanen KA, Lidell ME, Heglind M,Westergren R, Niemi T, van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Diabetes sex ofbrown andadiposity with inhumans. relationships adiposetissue Reimold M, &Stefan N. Haring HU, Claussen CD Impact ofage onthe NEJMoa0810780) Journal ofMedicine ofbrown inadulthumans. importance adiposetissue Kuo FC, Palmer EL, Tseng YH, Doria A 360 inhealthy adults. adipose tissue Taittonen M, Laine J, Savisto NJ, Enerback S NEJMoa0808718) Journal ofMedicine brownCold-activated inhealthy men. adiposetissue Kemerink GJ, Bouvy ND,Drossaerts JM, Schrauwen P &Teule GJ. In summary, hyperthyroidism isoften associated with 1518–1525. 2010 2010 59 (https://doi.org/10.1056/NEJMoa0808949) 1789–1793. 2009 2009 2009 360 360 Downloaded fromBioscientifica.com at10/02/202103:29:12PM 1509–1517. 1500–1508. (https://doi.org/10.2337/db10-0004) New EnglandJournal ofMedicine New https://eje.bioscientifica.com et al (https://doi.org/10.1056/ (https://doi.org/10.1056/ . Identification and . Identification et al 185 . Functional brown. Functional :4 New England New New England New 18 F-FDG PET F-FDG 561 2009 2009 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com

20 12 10 18 19 15 13 17 16 14 11 9 8 7 6 5 Clinical Study Lahesmaa M, Orava J, Soinio M, Hannukainen JC, Schalin-Jantti C, Zemskova M, Celi FS,Mueller E, Malek R,Hugendubler L,Skarulis MC, Lee JY, Takahashi N, Yasubuchi M, Kim YI,Hashizaki H,Kim MJ, Golozoubova V, Cannon B,Vennstrom B Gullberg H,Matthias A, & regulation. hormonal andtheir Silva JE. Thermogenic mechanisms Yau WW, Singh BK,Lesmana R, Zhou J, Sinha RA, Wong KA, Wu Y, Weiner J, Steinhoff K, Kunath A, Rijntjes E, Kranz M, Kloting N, Ribeiro MO, Bianco SD, Kaneshige M, Schultz JJ, Cheng SY, Bianco AC de Jesus LA, Carvalho SD, Ribeiro MO, Kim SW, Schneider M, Bianco AC, Maia AL,daSilva WS &Christoffolete MA. Adaptive Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Bianco AC &Kim BW. localcontrol Deiodinases:implications ofthe Brown milestones research ofapotential Zafrir B. adiposetissue: Bruns OT,Bartelt A, Peldschus K, Reimer R, Hohenberg H,Ittrich H, &Heeren J.Bartelt A The holy disease:brown ofmetabolic grail Matsushita M, Yoneshiro T, Aita S,Kameya T, Sugie H&Saito M. Hyperthyroidism increases brownHyperthyroidism inhumans. fatmetabolism Noponen T, Kirjavainen A, Iida H,Kudomi N, Enerback S Metabolism extreme insulinresistance. with ofdiabetesbrown andamelioration inapatient adiposetissue Solomon J,Cochran C, Chen C & Gorden P. Thyroid induced hormone (https://doi.org/10.1152/ajpcell.00010.2011) Journal ofPhysiology:American Cell Physiology expression biogenesis inhumanadipocytes. andmitochondrial Sakamoto T, Goto T & Kawada T. Triiodothyronine inducesUCP-1 doi.org/10.1210/me.2003-0267) receptors. hormone inmicedevoid recruitment thyroid tissue ofallhormone-binding Nedergaard J. but competent Depressed thermogenesis brown adipose physrev.00009.2005) Physiological Reviews 080/15548627.2018.1511263) mediated mitophagy. biogenesis andMTOR- viamitochondrial activation adipose tissue Bay BH, Sugii S,Sun L Reports expenditure. andenergy ofthyroid hormone activation org/10.1038/srep38124) inmice. adipose tissues andbrowningstatus definesbrowntissue activity of adipose white Kohrle J, Zeisig V, Hankir M,Gebhardt C (https://doi.org/10.1038/nm.2207) balance. ofenergy regulation et al Velagapudi VR, Morgan DA, Agassandian K, Lage R Schoenmakers E, (https://doi.org/10.1210/en.2009-0667) required for adaptive thermogenesis. receptor-beta isthyroid hormone adipose tissue isoform specificand & Brent GA. Expression ofuncouplingprotein 1inmousebrown doi.org/10.1172/JCI13803) tissue. for inbrowndeiodinase isessential adaptive adipose thermogenesis Harney JW, &Bianco AC. Larsen PR The type2iodothyronine 2571–2579. action. of thyroid hormone Research player balanceandobesity. inhumanenergy 200–205. controls triglyceride activity clearance. tissue Tromsdorf UI,Kaul MG, Weller H, Waurisch C doi.org/10.1097/MOL.0b013e328352dcef) adipose tissue. 812–817. inhealthy humans. metabolism Impact ofbrown onbodyfatnessandglucose adiposetissue . Hypothalamic AMPK and fatty acid metabolism mediate AMPKandfattyacidmetabolism thyroid . Hypothalamic Journal ofClinicalInvestigation 2005 2005 2013 2013 (https://doi.org/10.1038/ijo.2013.206) (https://doi.org/10.1038/nm.2297) 2010 2010 (https://doi.org/10.1172/JCI29812) 25 45 Current OpinioninLipidology 191–208. 774–785. 95 256–262. 2006 2006 Molecular Endocrinology Autophagy et al Scientific Reports Scientific (https://doi.org/10.1007/s10540-005-2885-6) . Thyroid (T3) stimulates brown hormone 86 (https://doi.org/10.1055/s-0033-1348264) Journal of Clinical Endocrinology and Journal ofClinicalEndocrinology Journal ofClinicalInvestigation 435–464. 435–464. Nature Medicine (https://doi.org/10.1210/jc.2009-0543) 2019 2019 International JournalofObesity International 2001 2001 Endocrinology 15 L Sunandothers (https://doi.org/10.1152/ 2016 2016 131–150. et al 108 2012 2012 2004 2004 2012 2012 . Thyroid hormone 2010 2010 Hormone andMetabolic Hormone 6 Nature Medicine 1379–1385. et al 38124. 23 18 302 (https://doi.org/10.1 . Brown adipose 2010 2010 16 190–195. 384–401. 1001–1008. (https://doi. C463–C472. Bioscience Bioscience 151 et al 2006 2006 (https:// 432–440. 432–440. 201 011 2 . (https:// Journal (https:// 2014 2014 116 17

38

Brown fatandthyroidstatus 26 25 23 22 33 32 30 29 28 34 24 27 21 31 Zhang Q, Miao Q, Ye H, Miao Q, Zhang Q, Zhang Z,Zuo C,Hua F, Guan Y&Li Y. The Sadananthan SA, Prakash B, Leow MK,Sadananthan SA, Khoo CM,Chou H, Hu HH, Bornert P, Hernando D, Kellman P, Ma J, Reeder S &Sirlin C. Hernando D, Kellman P, Haldar JP&Liang ZP. Robust water/fat Sun L, Verma S, Chan SP, Michael N, Yan J, Sadananthan SA, Sun L, Yan J, Goh HJ, Govindharajulu P, Verma S, Michael N, Goh HJ, Govindharajulu P, Camps SG, Tan SY Gross and &Henry CJ. Kyriacou A, Kyriacou A, Makris KC, Syed AA &Perros P. Weight gain Lonn L, Stenlof K, Ottosson M, Lindroos AK, Nystrom E &Sjostrom L. Sun L, Camps SG, Goh HJ, Govindharajulu P, Schaefferkoetter JD, Chen KY, Hu HH,Bredella MA, Cypess AM,Laughlin MR,Haft CR, Leitner BP, Baskin AS,McGehee S, Duckworth CJ, Huang S,Brychta RJ, McCallister A, Zhang L,Burant A, &Branca RT. Katz L Apilotstudy on Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S,Gee JC&Gerig G. doi.org/10.1002/mrm.22177) cut algorithm. presencegraph oflarge fieldinhomogeneities usinga inthe separation 1434–1442. (TACTICAL-II).and whole-body calorimetry evaluation by multimodality PET,tissue: MRI,infrared thermography, Camps SG, Goh HJ, Govindharajulu P, Totman J dgaa005) Metabolism brown activation. adiposetissue factor-21, responses to acute cold-induced andadiponectin leptin, Velan SS Henry CJ, Sadananthan SA, &Leow MK. Fibroblast growth org/10.1038/ejcn.2016.134) European Journal ofClinicalNutrition inAsianmen. relative cost householdactivities ofdomestic energy 513–520. a PET-CT study. thyroid onbrowneffectstissue inhumans: of hormones adipose org/10.1210/jc.2013-2312) andMetabolism of ClinicalEndocrinology Obesity following treatment ofhyperthyroidism-A forgotten tale. 83 hyperthyroidism. Body weight andbodycomposition after changes treatment of doi.org/10.1093/ajcn/nqx025) scan. in BAT-positive humansconfirmed by positron emission tomography 18-fluorine subthreshold associated with fluorodeoxyglucose uptake brownactivate (BAT) adiposetissue expenditure increased energy with Townsend DW, Verma SK, Velan SS, Sun L,Sze SK jmri.24655) Magnetic Resonance Imaging and tissues innormal overweight adipose superficial) men. ofvisceral (deepand andsubcutaneous Automated segmentation Venkataraman K, Khoo EY, Lee YS, Gluckman PD, Tai ES 2016 for inhumans. standardized FDG-PET/CTexperiments inimagingSTudies criteria reporting (BARCIST 1.0): recommendations Lichtenbelt Wv,Enerback S, Kinahan PE, Lin FI 8649–8654. brown inleanandobeseyoung adiposetissue men. Tal I, Dieckmann W, Kolodny GM Gupta G, Medicine in supraclavicular fatby PET/MRI. simultaneous between values fatfraction andglucoseuptake values correlation the 1116–1128. improvedsignificantly efficiencyand reliability. User-guided ofanatomical structures: 3Dactive contour segmentation (https://doi.org/10.1002/mrm.24369) inMRI. progress ISMRM workshop onfat-water and insights, separation: applications 4269–4273. 24 American Journal ofClinical Nutrition American 2019 2019 210–222. 2017 2017 (https://doi.org/10.1002/dmrr.2556) (https://doi.org/10.1016/j.neuroimage.2006.01.015) 2020 (https://doi.org/10.1002/oby.22560) (https://doi.org/10.1073/pnas.1705287114) 9 78 e12328. Magnetic Resonance inMedicine (https://doi.org/10.1210/jcem.83.12.5338) Diabetes/Metabolism Research andReviews Magnetic Resonance inMedicine 1922–1932. 105 (https://doi.org/10.1016/j.cmet.2016.07.014) Journal of Clinical Endocrinology andMetabolism Journal ofClinicalEndocrinology e520–e531. (https://doi.org/10.1111/cob.12328) 2015 2015 Downloaded fromBioscientifica.com at10/02/202103:29:12PM (https://doi.org/10.1002/mrm.26589) 41 Journal of Clinical Endocrinology and Journal ofClinicalEndocrinology (https://doi.org/10.1210/clinem/ 924–934. 2016 2016 2014 2014 70 2018 2018 185 et al 1414–1419. Obesity 99 2010 2010 (https://doi.org/10.1002/ 2012 2012 107 et al E28–E35. . Mappingofhuman et al :4 Neuroimage Magnetic Resonance in et al 63 62–70. . Brown adipose PNAS 2019 2019 . Brown adipose 68 . Capsinoids 79–90. Cell Metabolism 378–388. (https://doi. et al 2014 2014 2017 2017 27 Clinical (https://doi. (https:// Journal of 2006 2006 .

(https:// 30 114 562 1998

31 via freeaccess

European Journal of Endocrinology

44 43 45 42 40 39 38 36 35 41 37 Clinical Study Blondin DP, Phoenix S,Guerin B, Labbe SM,Noll C, Kunach M, Wu M, Junker D, Branca RT &Karampinos DC. Magnetic Koskensalo K, Raiko J, Saari T, Saunavaara V, Eskola O, Nuutila P, Blondin DP, Tingelstad HC, Noll C, Frisch F, Phoenix S,Guerin B, Cypess AM, Chen YC, Sze C,Wang K, English J, Chan O, Holman AR, Yoneshiro T, Aita S, Kawai Y, Iwanaga T &Saito M. Nonpungent Lim AY,Chng CL, Tan HC, Kovalik JP, Tham KW, Bee YM,Lim W, Dutta P, Bhansali A,Walia R, Khandelwal N, Das S&Masoodi SR. Tata JR, Ernster L &Lindberg O. Control rate ofbasalmetabolic by control E&Burger A. The inthe roleDanforth Jr ofthyroid hormones Greenlund LJ, Nair KS &Brennan MD. Changes inbody brown adipose tissue of subjects with type 2diabetes.brown ofsubjects with adiposetissue impairment ofglucosebutnotfattyacidoroxidative in metabolism Turcotte ÉE, Haman F, Selective &Carpentier AC. Richard D Communications fendo.2020.00421) Frontiers inEndocrinology resonance imagingtechniques for brown detection. adiposetissue (https://doi.org/10.1210/jc.2016-3086) andMetabolism Journal ofClinicalEndocrinology temperature are related andfatfraction to its activity. metabolic Saunavaara J, Parkkola R &Virtanen KA. Humanbrown adiposetissue 2388–2397. men. ofbrownmetabolism incold-acclimated adiposetissue Turcotte ÉE, fattyacid Richard D, Dietary Haman F&Carpentier AC. 10001–10005. humanbrownactivates invivo. adiposetissue Tal I, Palmer MR, Kolodny GM ajcn.111.018606) of ClinicalNutrition ofbrown inhumans. adiposetissue activation the expenditure capsaicin analogs(capsinoids)increase energy through org/10.1089/thy.2015.0602) in Graves’ disease. transitionfrom hyperthyroidism to euthyroidism the during changes Lai OF,Acharyya S, Chong MF 2012 and after carbimazole. treatment with Weight homeostasis andits inhyperthyroidism modulators before org/10.4158/EP.14.8.973) hyperthyroidism. composition inwomen following treatment ofovert andsubclinical (https://doi.org/10.1038/1931058a0) andcellularfunction. thyroid hormones 581–595. expenditure.of energy 136 242–248. (https://doi.org/10.1016/s0300-595x(84)80039-0) (https://doi.org/10.2337/db14-1651) (https://doi.org/10.1073/pnas.1207911109) 2017 2017 Endocrine Practice Endocrine Thyroid 2012 2012 8 Clinics in Endocrinology andMetabolism Clinics inEndocrinology 14146. 2020 95 2016 2016 845–850. 845–850. 11 (https://doi.org/10.1038/ncomms14146) et al et al 26 421. 1422–1430. . Physiological andmetabolic . Cold but not sympathomimetics . Coldbutnotsympathomimetics 2008 2008 (https://doi.org/10.3945/ (https://doi.org/10.3389/ Indian Journal ofMedicalResearch L Sunandothers Nature 14 973–978. PNAS 2017 2017 (https://doi. 1962 American Journal American 2012 2012 102 193 Diabetes (https://doi. 1200–1207. 1058–1060. 109 Nature 1984

2015 2015 13 64

Accepted 3August2021 Revised versionreceived10June2021 Received 8April2021

Brown fatandthyroidstatus 52 48 46 56 55 50 49 53 54 47 51 Broeders EP, Vijgen GH, Havekes B, Bouvy ND, Mottaghy FM, Kars M, Masini M, DeTata V, DelRoso A, Pollera M Simonetti I, &Bergamini E. balance. Silva JE. andenergy Thyroid control ofthermogenesis hormone Hu HH, Branca RT, Hernando D, Karampinos DC, Machann J, Junker D, Syvari J, Weidlich D, Holzapfel C, Drabsch T, Waschulzik B, Sun L, Goh HJ, Govindharajulu P, &Leow MK. Sun L,Henry CJ Silva JE Potential &Larsen PR. ofbrown type adipose tissue Santhanam P, Ahima RS,Mammen JS,Giovanella L &Treglia G. Brown Kovanicova Z, Kurdiova T, Balaz M,Stefanicka P, Varga L, Kulterer OC, Gavrila A, Hasselgren PO, Glasgow A, Doyle AN, Lee AJ, Fox P, Mullur R, Liu YY&Brent GA. Thyroid of regulation hormone Thyroid brown activates andincreases hormone adiposetissue Schrauwen P,Schaper NC, Brans B &van Marken Lichtenbelt WD. bqaa051. humans. andnon-acclimatized acclimatized distinctively modulates parathyroid incold- andthyroid hormones study.ultrastructural The brown and ofhyperthyroid rats: abiochemical adiposetissue Thyroid (https://doi.org/10.1002/mrm.28103) ISMRM workshop. 2019 from the imaging ofobesity summary disorders: andmetabolic McKenzie CA, Wu HH, Yokoo T &Velan SS. resonance Magnetic org/10.1159/000507294) thyroid hormones. betweenrelationship MR-based supraclavicular and fatfraction Rummeny EJ, Hauner H&Karampinos DC. Investigation ofthe org/10.1038/s41598-020-66697-0) thermoregulation. thyroid-brownA feedforward the fat axisfacilitates loopwithin 2296–2305. inrats. triiodothyronine II thyroxine 5 org/10.1007/s12020-018-1698-x) level(s)-a systematic review. (BAT)adipose tissue by detection (18)F-FDG PETandthyroid hormone org/10.1371/journal.pone.0145049) carcinoma patients. study ofthyroid inagroup acohort non-shivering thermogenesis: Betz MJ, Haug AR,Burger IA, Kiefer FW Thyroid induced brown response status. to thyroid hormone adiposetissue Hennessey JV,Gautam S, Kolodny GM &Cypess AM.Variable cold- org/10.1152/physrev.00030.2013) metabolism. 27–34. 1995 (https://doi.org/10.1016/0303-7207(90)90041-6) 2017 2017 (https://doi.org/10.1210/endocr/bqaa051) (https://doi.org/10.1172/JCI112239) 5 Physiological Reviews 27 ′ 481–492. -deiodinase asalocalandsystemic source of 1–10. Magnetic Resonance inMedicine Scientific Reports Scientific Obesity FactsObesity PLoS ONE Molecular andCellular Endocrinology (https://doi.org/10.1089/thy.2015.0646) (https://doi.org/10.1089/thy.1995.5.481) Journal ofClinicalInvestigation Downloaded fromBioscientifica.com at10/02/202103:29:12PM Endocrine 2016 2016 2020 2014 2014 2020 11 https://eje.bioscientifica.com 2018 2018 13 e0145049. 94 et al 331–343. 10 355–382. 62 . Coldexposure 9661. 185 Endocrinology 496–500. 496–500. :4 2020 (https://doi. (https://doi. (https://doi. (https://doi. 1985 83 (https://doi. 1990 1565–1576. 2020 76 73

563 161 via freeaccess