European Journal of Endocrinology 10.1530/EJE-16-0958 Introduction role ofBAT inappetiteregulationhumans. to elucidatethepotentiallinkofBAT withthepostprandiallevelsofappetite-regulating peptidesandtheputative regulation, suggestingapotentialcrosstalkbetweenBAT andtheenteropancreaticaxis. Furtherstudiesareneeded Conclusions BAT activationwassignificantly associated withlowerserumghrelinconcentration( percent. CEsignificantlydecreasedserumleptin( via uncoupling protein 1 (UCP1) in response to various associated metabolic perturbations ( againstobesityanditsputative targetforinterventions tissue inhumans( Brown adiposetissue(BAT), arecentlyrediscovered ( Results appetite regulationweremeasuredduringthermoneutralconditionsandmildCE. after mildcoldtomeasureBAT volume. FastingserumconcentrationofGI-secretedpeptidesandinvolvedin Methods Design appetite regulationisnotknowninhumans. The relationbetweenBAT andpeptide hormonessecretedfromthegastrointestinalsystem(GI)andinvolvedin related metabolicconditions.DatafromstudiesinrodentssupportacrosstalkbetweenBAT andotherdistaltissues. Objective Abstract New Jersey, USA Branch, Galveston,Texas, USA,and 5 Medicine, StLouis,Missouri,USA, 3 Sciences, DepartmentofNutritionandMetabolism,UniversityTexas MedicalBranch,Galveston,Texas, USA, 1 and Maria Chondronikola involved inappetiteregulation from thegastrointestinal systemand systemic concentrationsofpeptidessecreted Brown adiposetissueisassociatedwith Department ofSurgery, Center forHumanNutritionandAtkinsofExcellenceinObesityMedicine,Washington UniversitySchoolof Metabolism Unit,ShrinersHospitalsforChildren-Galveston,Galveston,Texas, USA, P DOI: 10.1530/EJE-16-0958 www.eje-www.eje-online.org
Clinical Study = Labros S Sidossis 0.006), gastricinhibitorypolypeptide( : We studied18menduringthermoneutralconditionsandmildnon-shivering coldexposure(CE). : Duringthermoneutralconditions,BAT volumewasassociatedwithlowerserumconcentrationofleptin online.org : 2-Deoxy-2-( : Brownadiposetissue(BAT) has beenproposedasapotentialtherapeutictargetagainstobesityandits : BAT isassociatedwithsystemic concentrations ofGI-secretedpeptidesandinvolvedinappetite
6 Division ofPediatricEndocrinology, DepartmentofPediatrics,UniversityTexas Medical 1 , 18 1 1 2 F)fluoro- , , 2 2 , , , 4 3 3 , , 5 4 4 , Department ofNutritionandDietetics,HarokopioUniversity, Athens,Greece, , , Craig Porter 7 7 Department ofKinesiologyandHealth,RutgersUniversity, NewBrunswick, 4 © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology ), hasbeenproposedasa d -glucose positronemissiontomography-computedtomographyscanswereconducted M Chondronikolaandothers 5 ). Thermogenesis 1 Printed inGreatBritain P , 5
= , Ioannis Malagaris 0.016) andglucagon( P
= 0.004) andglucagonconcentration( ( regulation viaalternative non-thermogenic pathways BAT hasalsobeenproposed tocontributemetabolic functionofBATthe primary ( stimuli (coldandfoodingestion) isconsideredtobe BAT andGI-secretedpeptides 7 Published byBioscientifica Ltd. ). Datafromepidemiological studiessupportthat 1 2 , 2 Division ofRehabilitation , Aikaterini A Nella P
= 0.048) afteradjustingforageandbodyfat P =0.029). Downloaded fromBioscientifica.com at09/26/202101:27:00PM 1 , 6 P
.2) wie cold-induced while =0.020), 6 (2017) Endocrinology European Journal of [email protected] Email to LSSidossis should beaddressed Correspondence ), whilemorerecently 177 177 : 1 177 :1 , 33–40
33 –40 via freeaccess European Journal of Endocrinology whereas datafromrodentstudiessupportalinkbetween glucocorticoids ( ‘intrascapular gland’)( regulation, whereasBAT (sometimesreferredtoasthe numerous circulating peptidesaffectBAT metabolic kinetics andthermoregulation havebeenpreviously glucose metabolism,insulin sensitivity, freefattyacid characteristics of theparticipants. Outcomesrelatedto were enrolled in the study. Eighteen men(age47.6 Subjects Subjects andmethods endocrine roleforBAT inhumans. regulation andenergyhomeostasis,suggestingapotential adipose tissue-secretedpeptidesinvolvedinappetite these resultssupportalinkbetweenBAT andkeyGI which wasindependentofageandadiposity. Overall, suppression in serum ghrelin concentration during CE, Moreover, BAT volumewasassociatedwithgreater decreased comparedtothermoneutralconditions. thermogenesis, serum leptinandglucagon concentration thermoneutrality. When mild CE was used to activate BAT polypeptide(GIP)andglucagonduring gastric inhibitory associated withlowerserumconcentrationsofleptin, of age and adiposity, BAT volume was significantly BAT levels). Our findings support that, independent (peptides linkedtoimpairedBAT functionand/orlower systemic concentrationsofleptin,ghrelinandglucagon We hypothesizedthat BAT wouldbeassociated with lower thermoneutral conditionsandmildcoldexposure(CE). regulation isnotknowninhumans. peptides involvedinenergyhomeostasisandappetite However, therelation(ifany)betweenBAT andkey system (GI)involvedinappetiteregulation( BAT and peptides secreted from the gastrointestinal thyroid hormones ( ( that mayaffectmetabolicregulationinothertissues ( and oxidation,glucosedisposalinsulinsensitivity energy expenditure,acceleratedlipidmobilization induced BAT activationhasbeenlinkedtoincreased and metabolichealthinpeople( higher amountsofBAT areassociatedwithleanness www.eje-online.org 6 3 , Clinical Study , 17 10 To addressthis,westudied18menduring Data fromstudiesinrodentsdemonstratethat ). Studiesinpeoplehavealsoreportedtheeffectof , 11 , 12 , 13 21 , 14 ) andinsulin( 18 , , 15 19 ± 16 ).
17.8 years, BMI29.7 ), beta-adrenergic agonists ( ) secretessignalingmolecules Table 1 M Chondronikolaandothers 22 contains the descriptive 1 , ) onBAT metabolism, 8 , 9 ), whereascold- ± 6 4.9kg/m , 17 , 23 20 2 ). ), )
Medical Branch(UTMB)InstitutionalReviewBoardand with theDeclarationofHelsinki.TheUniversityTexas to studyenrolmentfromallparticipantsinaccordance excluded. Informedwrittenconsentwasobtainedprior with acute illnessor/and major chronic disease were use, andrecentmedicationorsupplementuse.Individuals were screenedforhealthstatus,smoking,alcoholordrug reported (NCT01791114)( study, theparticipants worethesamestandardized needed topreventshivering. Duringthethermoneutral temperatures wereincreased by1°Candadjustedas reported shivering.Then,cooling garmentandambient approximately 19–20°Candweredecreaseduntilsubjects the coolinggarmentsandroomwereinitiallyset at Stow, OH,USA)andlaidsupine.Thetemperatures of and Arctic Chillercooling system, Polar Products Inc., cooled byliquidcirculation (CoolFlowvestandblanket described ( to inducenon-shiveringthermogenesisaspreviously morning, a6-hindividualizedCEprotocolwasemployed and apairofshorts).DuringtheCEstudy, the following bed overnight, wearing standardized clothing (a T-shirt offered astandardizedmeal.Subjectsfastedandrestedin admitted totheITSClinicalResearch CenteratUTMBand and caffeine.Theeveningbeforeeachstudy, subjectswere excessive physicalactivityandconsumptionofalcohol follow aweight-maintainingdietandalsorefrainfrom Three daysbeforethestudy, participantswereaskedto thermoneutral study, approximatelytwoweeksapart. Each participantcompletedoneCEstudyand Experimental protocol April 2015. 2012until study participantswereenrolledfromJanuary Committee approvedtheexperimentalprotocol.The Institute forTranslational Sciences(ITS)ScientificReview standardized uptakevalue. BAT, brownadiposetissue;BMI,bodymassindex;SUV Serum insulin( Plasma glucose(mg/dL) BAT SUV BAT volume(mL) Body fat(%) Lean mass(kg) BMI (kg/m Age (years) Parameters Table BAT andGI-secretedpeptides 1
mean Subject characteristics. 2 ) 11 (g/mL) ). Briefly, duringCE,subjectsworegarments μ U/mL) Downloaded fromBioscientifica.com at09/26/202101:27:00PM 11 , 15 , 24 ). Studyparticipants 177 :1 97.8 1.67 33.9 32.4 61.9 29.7 47.6 Mean 8.4 mean ± ± ± ± ± ± ± ± , mean ± 5.7 8.4 0.99 43.3 9.1 8.3 4.9 17.8
s . d . 34 via freeaccess European Journal of Endocrinology Pasadena, CA,USA)andplasma glucoseconcentrations chemiluminescence (Dxi600 analyzer; BeckmanCoulter, Serum insulinconcentrations weremeasuredusing of variationwere the statisticalanalysis.Intra-andinterassaycoefficients assay, theupperlimitofdetectablelevel wasusedin serum concentrationsbelowthedetectablelevelsof assay (Milliplex,Billerica,MA,USA).Forsampleswith (MinDC: 28 polypeptide (PP)(MinDC:2 1.2 active glucagon-likepeptide1(GLP1)(MinDC: peptide(GIP)(MinDC: 0.6 gastric inhibitory (MinDC): 41 Serum leptin (minimum detectable concentration Blood sampleanalysis QDR-4500W, Hologic Inc., Bedford,MA,USA). mass andfatfreeoftheparticipants(Hologicmodel We toevaluatethefat usedDualX-rayAbsorptiometry Body composition individual BAT deposit(withaSUV BAT wasquantifiedbyautocontouringeachidentified Corp., Cleveland,OH,USA).Thevolumeof commercial fusionsoftware (MIMsoftware;MIMvista SUVs for each identified depositweredetermined using tissue onCT(−190to−30Hounsfieldunits).Themean and (c) the tissue corresponded to the density of adipose 1.5 orgreater(anindicatorof perirenal areas;(b) supraclavicular, mediastinal,paravertebraland/or criteria: (a) the PET–CTscansfor standardized uptakevalue(SUV; g/mL).We assessed performed toassessBAT volume(mL)andmean Medical Systems,Milwaukee,WI,USA)scanwas computed tomography(PET–CT)(GeneralElectric One hourlater, apositronemissiontomography– 185 After 5 tomography (PET–CT) Positron emissiontomography–computerized at 25–27°C. clothing, andtheambientroomtemperaturewaskept Clinical Study pg/mL), glucagon(MinDC:13 MBq of2-deoxy-2-( h ofCE,subjectsweregivenabolusinjection 18 pg/mL) weremeasuredusingamultiplex pg/mL), activeghrelin(MinDC:13 F-FDG uptake was evident in the cervical– 18 F-FDG uptakehadameanSUVof < 18 10% and F-FDG BAT usingthefollowing 18 F)fluoro- pg/mL) andpeptideYY(PYY) 18 F-FDG uptakeintensity) M Chondronikolaandothers d < ≥ pg/mL), pancreatic -glucose ( 15%, respectively. 1.5). 18 18 pg/mL), pg/mL), F-FDG). F-FDG
due tothesmallsampleofstudy. Correction formultiplecomparisonswasnotperformed All statisticaltestsassumeda95%levelofconfidence. was performedusingSPSSstatisticalsoftware,version23. better centeringandinterpretation.Thestatisticalanalysis percent andage.BAT volumewaslog-transformedfor for thepotentiallyprognosticcovariatesofbodyfat between eachoutcomeandBAT volume,whileadjusting Multivariate linearregressionmodeledtherelationship concentrations ofthepeptidehormonesinterest. to evaluate the association of BAT volume with serum and multivariateregressionanalyseswereperformed between CEandthermoneutralconditions.Univariate Paired Statistical analysis (Yellow SpringInstruments,Yellow Springs,OH,USA). were measuredusinganautomatedglucoseanalyzer of CEsignificantlydecreased serumleptin( homeostasis andappetiteregulation ( of secretedpeptidesinvolved intheregulationofenergy shivering coldandaccessed the circulating concentrations Therefore, we exposed the study participants to mild, non- against metabolic abnormalities. a lifestyleintervention Decreasing ambienttemperaturehasbeenproposed as Mild CEdecreases glucagon andleptinconcentrations age andadiposity( marginally associatedwithBAT volumeafteradjustingfor ( ( associated withlowerserumleptin( with elevatedPYYconcentration,butitwassignificantly percentage andage,BAT volumewasnolongerassociated On multivariateanalysis,andafteradjustingforbodyfat leptin ( associated withhigherserumPYY( ( energy homeostasisduringthermoneutralconditions secreted peptidesinvolvedinappetiteregulationand the relationshipofBAT volumewithGIandadipocyte- We usedunivariateandmultivariateanalysistoidentify leptin, GIPandglucagonduringthermoneutrality BAT isassociatedwithlowerserumconcentrationsof Results BAT andGI-secretedpeptides i. 1A, Fig. P 2 Table
= 0.016) andglucagon( t P -tests wereusedtocompare the hormonelevels
). Byunivariateanalysis,BAT volumewas < B
0.001) andinsulinconcentrations( and C P ). Seruminsulinconcentrationwas =0.084). Downloaded fromBioscientifica.com at09/26/202101:27:00PM P .4) concentrations =0.048) P 177 Table 3 .1) n lower and =0.013) www.eje-online.org :1 P .0) GIP =0.006), ). Fivehours P P =0.025). =0.004) 35 via freeaccess European Journal of Endocrinology www.eje-online.org Values inboldfontdenotestatisticalsignificance. For themultivariateregression,estimateshavebeenadjustedforageand%bodyfat.BAT volumeshavebeentransformedaslog(BAT volume Insulin ( Peptide YY(pg/mL) Leptin (pg/mL) Pancreatic polypeptide(pg/mL) Glucagon-like peptide1(pg/mL) Glucagon (pg/mL) Gastric inhibitorypolypeptide(pg/mL) identify therelationbetweenBAT volumeandchange Univariate andmultivariateanalyseswerealsousedto serum ghrelin concentration BAT activationbyCEisassociatedwithdecreases in thermoneutral conditions. and glucagon( Ghrelin (pg/mL) Parameters energy homeostasisandappetiteregulationduringthermoneutrality. Table 2 Clinical Study
μ U/mL) Association betweenbrownadiposetissue(BAT) volumewiththesystemicconcentrationsofpeptidesinvolvedin P
= 0.020) concentrations compared to M Chondronikolaandothers −5748 52.8 −3.7 −6.8 −5.1 −5.9 Univariate Beta 1.9 8.3
± ± ± ± ± ± ± ±
±
13.1 4.3 10.3 10.4 4.2 1204 1.5 18.7
s . e . concentration withCEcomparedtothermoneutral associated withagreatersuppressioninserumghrelin and bodyfatpercentage) showedthatBAT volumewas however, multivariate analysis (after adjusting for age analysis, nopositiveornegativeassociationswerefound; in peptidehormonesduringCE( between BAT volumeandthecold-inducedchangein conditions ( BAT andGI-secretedpeptides <
P 0.025 0.013 0.001 0.608 0.674 0.630 0.577 0.067 -value
P .2) ( =0.029) exposure ( percent bodyfatinresponseto cold concentration adjustedforage and with thechangeinserumghrelin conditions. (D)AssociationofBAT volume body fatpercentduringthermoneutral (C) leptin( ( (A) gastricinhibitorypeptide(GIP) volume withtheserumconcentrationof appetite. (A,BandC)AssociationofBAT regulating energyhomeostasisand serum concentrationsofpeptides Association betweenBAT volumewiththe Figure 1 P −4467 −26.7 −33.6
= Multivariate −4.1 38.6 2.96 12.2 0.016), (B)glucagon( Beta 3.1 Fig. 1D Downloaded fromBioscientifica.com at09/26/202101:27:00PM
± ± ± ± ± ± ± ±
± 2.1 28.5 19.90 6.2 6.3 1375 12.3 12.3 P P
s . =0.029).
= e ). Therewasnoassociation . 0.006) adjustedforageand Table 4 177 :1 ). Onunivariate P .4) and =0.048)
0.006 0.048 0.016 0.084 0.200 0.884 0.545 0.074 P -value
+ 1). 1). 36 via freeaccess European Journal of Endocrinology Values inboldfontdenotestatisticalsignificance. The estimateshavebeenadjustedfor ageand%bodyfatinthemultivariateregression.BAT volumeshavebeen transformedaslog(BAT volume Insulin ( Peptide YY(pg/mL) Pancreatic polypeptide(pg/mL) Leptin (pg/mL) Glucagon-like peptide1(pg/mL) Glucagon (pg/mL) Gastric inhibitorypolypeptide(pg/mL) Ghrelin (pg/mL) Parameters peptides regulatingenergyhomeostasisandappetiteregulation. Table 4 Values inboldfontdenotestatisticalsignificance. Insulin ( Peptide YY(pg/mL) Pancreatic polypeptide(pg/mL) Leptin (pg/mL) Glucagon (pg/mL) Glucagon-like peptide1(pg/mL) Gastric inhibitorypolypeptide(pg/mL) ghrelin concentrationwithCE;duringthermoneutrality, BAT volumewasassociatedwiththesuppressioninserum and, theorexigenicguthormone( role ofBAT inhumans. metabolic regulationbysuggestingapotentialendocrine Collectively, theseresultsfurtherdefinetheroleofBAT in decreased serumconcentrationsofleptinandglucagon. concentration with CE. Finally, CE was associated with associated withagreatersuppressioninserumghrelin during thermoneutralconditions.BAT volumewasalso GIP concentrations independent of age and adiposity was associatedwithlowerserumglucagon,leptinand energy metabolisminpeople.Specifically, BAT volume secreted peptidesinvolvedinappetiteregulationand the systemicconcentrationsofGItractandadipose- We reportevidencesupportingalinkbetweenBAT and Discussion concentrations. serum insulin,GIP, glucagon,GLP1,leptin,PYYorPP Ghrelin (pg/mL) Parameters represent theserumconcentrationsin5-hCEandTNmetabolicstudies. exposure (CE)conditionsandtheirchangebetweenthetwoconditions.Dataarepresentedasmean Table 3 Clinical Study Our studyisthefirst toreport alinkbetweenBAT
μ μ U/mL) U/mL) Association betweenbrownadiposetissue(BAT) volumeandthecold-induced changeintheconcentrationofsystemic Systemic concentrationsofsecretedpeptidesregulatingenergyhomeostasisduringthermoneutral(TN)andcold M Chondronikolaandothers 25 ), ghrelininhumans. 8379 42.2 65.4 67.2 15.6 33.0 38.0 5.1 −0.7 −8.3 −0.2 −8.3 20.1 Univariate Beta 758 3.4 2.1
± ± ± ± ± ± ± ± TN 3.8 51.2 63.9 12.6 25.0 42.2 5153 28.3 ± ± ± ± ± ± ± ± ± 1.4 7.4 19.0 694 3.2 4.0 5.7 9.3
s . e . lower fastingghrelinconcentrations( targetinpatientswithobesitywhom interventional of BAT activationinappetiteregulationandapossible ghrelin. Thesefindingsmightsuggestapotentialrole BAT wasonlymarginallyassociatedwithelevatedserum blunted postprandialsuppressioninsystemicghrelin previously associated with obesity ( tissue functioninrodents.ElevatedGIPlevelshavebeen ( of ageandadiposity. GIPisanothergut-derivedhormone GIP concentrationduringthermoneutralityindependent ghrelin andBAT functioninpeople. mechanistic studiesareneededtoestablishlinkbetween ghrelin concentrationandBAT activityinpeople.Future, ( has beenshowntoimpairBAT functioninrodents exerts itsactioninadipocytes( growth hormone secretagogue receptor via which ghrelin the linkbetweenBAT andghrelin.BAT expresses the data fromstudiesinpreclinicalmodelsalsosupport contribute todysregulatedenergyintake.Inaddition, concentration ( BAT andGI-secretedpeptides 32 23 6580 34.5 55.5 55.5 17.7 35.5 27.7 ), which has been reported to play a role in adipose ), whichhasbeenreportedtoplayaroleinadipose , 4.7 In thisstudy, BAT volumewasassociatedwithlowerserum
31 P 0.376 0.281 0.307 0.291 0.308 0.955 0.719 0.381 -value CE
± ± ± ± ± ± ± ± ). These results suggest a link between the systemic ). Theseresultssuggestalinkbetweenthesystemic
2.7 40.6 44.6 17.2 24.1 26.2 4289 26.6 26 , 28 −28.8 ) aretypicallyseenandthoughtto 1591 Multivariate −1.5 46.3 −1799 Beta Paired change Downloaded fromBioscientifica.com at09/26/202101:27:00PM 2.2 0.6 5.0 5.1 −10.0 −11.7 −10.3 −7.7 −0.8 −2.5 2.1
± ± ± ± ± ± ± ± ± 2.1 10.7 25.7 978 6.2 4.9 8.8 11.9
± ± ± ± ± ± ± ± s . 2.4 22.9 62.3 10.6 18.4 30.1 e ± 2280 12.8 . 29
s . 33 d , . Absolutevalues , 30 177 34 ), whereasghrelin www.eje-online.org ), but information ), but information :1 26 , P 0.029 0.478 0.842 0.093 0.126 0.927 0.325 0.570 27 -value P 0.004 0.020 0.359 0.101 0.436 0.420 0.571 0.165 -value
) anda
+ 37 1). via freeaccess
European Journal of Endocrinology www.eje-online.org interest asatargettissuefor thetreatmentofobesity. to produceheatand,thus, BAT hasattractedsignificant BAT arecurrentlyunknown. mechanisms explainingthe linkbetweenglucagonand decreased circulating glucagonconcentration( rodents haveshownthatBAT transplantationleadsto Consistent withourresults,datafromstudiesin the roleofglucagoninappetiteregulation( glucose production ( of blood glucose concentration by regulating hepatic cold. Glucagon plays a major role in the regulation and thatitfurtherdecreasesduringexposuretomild thermoneutrality afteradjustmentforageandadiposity, is associatedwithhigherBAT volumeduring we foundthatlowerserumglucagonconcentration with serum glucagon concentration. Specifically, with overweight/obesity. activation may alleviate ‘leptin resistance’ in participants with BAT, ourfindingssuggestthatcold-inducedBAT Considering the currentliterature on thelinkofleptin ( CE suppressesleptinproductioninbrownadipocytes models supporttherelationofBAT withleptin.Namely, adults ( induced changesinleptinconcentrationsyounglean acclimated BAT wasinverselycorrelatedwithcold- CE. Similarly, Lee further decreaseinserumleptinconcentrationduring conditions independentofageandadiposity, anda lower serumleptinconcentrationduringthermoneutral leptin. We foundasignificantassociationbetweenBAT and BAT withthesystemicconcentrationofadipokine determined. between BAT andthecold-inducedlipolysisremainstobe ( is associatedwithgreateradiposetissuelipolysiscold Interestingly, wehavepreviouslyreportedthatBAT volume stimuli leadingtoimpairedBAT metabolicfunction. and/or decreasedlipolysisinresponsetotheadrenergic fasting serumGIPmaypromoteexcessivefataccumulation lipolysis forBAT thermogenesis( induced lipolysis( promote fattyacidsynthesisandtoinhibittheisoprotenol- express theGIPreceptor( and the intestinalconcentrationofGIP ( cold acclimationincreasedBAT massrelativetobodyweight on their relationship to BAT function is sparse. In rodents, 15 39 Clinical Study ). Whetherthecirculating GIPlevelsmediatethelink ), whileBAT atrophyincreasesleptinsecretion( BAT activationincreasesenergy expenditure( The resultsofthisstudyalsosupporttherelation Moreover, our results support the relation of BAT 10 ). Additionally, datafromstudiesinpreclinical 37 t al et , 38 40 . previously reported that cold- ). Considering the importance of ). Consideringtheimportanceof ). Human studies also support 36 ), while GIP has been shown to ), whileGIPhasbeenshownto 6 M Chondronikolaandothers , 15 ), it is likely that high ), itislikelythathigh 35 ). Adipocytes ). Adipocytes 3 42 , 14 ). The , 41 24 6 ). ). ). )
are neededtosystematicallyinvestigatetheroleofBAT BAT activationmayaffecttheappetite( described), whilechangesinnutrientavailabilitydueto affect appetitealsoBAT activity(aspreviously to thermogenesis.Moreover, numerouspeptidesthat compensate fortheincreasedenergyexpendituredue the cold-relatedincreaseinfoodintakemaynotfully body fatinhealthyadults( that coldacclimationincreasedBAT activityanddecreased individuals withCE( for increasedappetiteinasmallgroupofyounglean conditions ( weight comparedtoanimalskeptinroomtemperature the cold-exposedrodentshavesignificantlylowerbody unclear. AlthoughCEincreasesfoodintakeinrodents, the roleofBAT inappetiteregulationandfoodintakeis to beeffectiveforweightloss.Thecurrentevidenceon induce an isocaloric increase in food intake are unlikely thatincreaseenergyexpenditureand Interventions explain theroleofBAT in systemicmetabolicregulation. BAT andothermetabolically activetissuesmightpartially be fullyunderstood.Meanwhile, acrosstalkbetween exerts itsmetaboliceffects systematicallyremainto for BAT inhumans.The mechanism(s)viawhichBAT homeostasis, suggesting a potential endocrine role peptides involvedinappetiteregulationandenergy between BAT andkey GI and adipose tissue-secreted thermoneutrality. Overall,theseresultssupport alink serum leptinandglucagonconcentrationscompared to CE. Finally, non-shiveringCEsignificantly decreased greater suppressioninghrelinserumconcentrationwith percent, whileBAT was significantlyassociatedwitha GIP andglucagonafteradjustingforagebodyfat associated withlowerserumconcentrationofleptin, to bedetermined. the generalizabilityofstudyresultsinwomenremains study consistedofmaleparticipantsonly, andtherefore, regulation and food intake. Moreover, the sample of the peptides andsupporttheputativeroleofBAT inappetite establish the relation of BAT with the appetite-regulating homeostasis. Furthermechanisticstudiesareneededto talk betweenBAT andothertissuesregulatingenergy of participants,theymightsuggestapotentialcross are crosssectionalandcollectedfromasmallsample and theadipokineleptin.Althoughtheseobservations from theenteropancreaticaxis(ghrelin,glucagonandGIP) potential underlyingmechanisms. in appetiteregulationandfoodintakeclarifythe BAT andGI-secretedpeptides In conclusion,thisstudyshowsthatBAT volumeis Here, wereportthelinkofBAT withsecretedpeptides 35 ). Inhumans,Lee 10 ), whileYoneshiro Downloaded fromBioscientifica.com at09/26/202101:27:00PM 43 ). Theseresultssuggestthat t al et 177 . reportedatrend 44 :1 ). Futurestudies et al . reported 38 via freeaccess
European Journal of Endocrinology References the clinicalstudies. University ofTexas MedicalBranch,fortheirassistancewithperforming We alsothankElisabetBorsheim,Christina YfantiandNicholasMHurren, hormones. Thestudywasregisteredatclinicaltrials.gov(NCT01791114). Medical Branch,formeasuringtheconcentrationsofserumpeptide imaging; ManishKSarafandJohnOOgunbilege,UniversityofTexas Lung ResearchInstituteCentrefortheBAT assessmentusingPET/CT for performingthePET/CTscans;SebastienMLabbe,QuebecHeartand coverage ofthestudy. RajeshKumar, UniversityofTexas MedicalBranch and FernardoCessani,UniversityofTexas MedicalBranch,forthemedical of Texas MedicalBranch.We alsothankElenaVolpi, PalamAnnamalai acknowledge theeditorialassistanceofSarahToombs Smith,University Research CenterattheUniversityofTexas MedicalBranch.Theauthors administrative personnelattheInstituteofTranslational SciencesClinical The authorswanttothankthestudyparticipantsandnursing Acknowledgements was fundedbytheAlexanderSOnassisPublicBenefitFoundation. Independence Center (P30 AG024832)andtheSealyCenteronAging.MC Fund forBiomedicalResearch(66992),theClaudePepperOlderAmericans for Childrengrants(84090,85310),theJohnSealyMemorialEndowment Health, theAmericanDiabetesAssociation(1-14-TS-35),ShrinersHospitals Center forAdvancingTranslational Sciences,theNationalInstitutesof Clinical andTranslational ScienceAward (UL1TR000071)fromtheNational Sciences attheUniversityofTexas MedicalBranch,supportedinpartbya This studywasconductedwiththesupportofInstituteforTranslational Funding perceived asprejudicingtheimpartialityofthisstudy. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest 7 6 5 4 3 2 1 Clinical Study 546–559. physiological rolesbeyondheatgeneration. (doi:10.1152/physrev.00015.2003) physiological significance. (doi:10.3389/fendo.2015.00156) of brownadipocytesinhumans. (doi:10.1152/ajpendo.00691.2006) Physiology: EndocrinologyandMetabolism active brownadiposetissueinadulthumans. NEJMoa0808718) ofMedicine New EnglandJournal Teule GJ.Cold-activated brownadiposetissueinhealthymen. Drossaerts JM,KemerinkGJ,BouvyND,SchrauwenP& 360 adipose tissueinhealthyadults. Taittonen M,LaineJ,SavistoNJ,EnerbackS NEJMoa0810780) ofMedicine England Journal importance ofbrownadiposetissueinadulthumans. Kuo FC,PalmerEL,Tseng YH,DoriaA Kajimura S,SpiegelmanBM&Seale P. Brownandbeigefat: Cannon B&NedergaardJ.Brownadipose tissue:functionand Porter C,ChondronikolaM&SidossisLS.Thetherapeuticpotential Nedergaard J,BengtssonT&CannonB.Unexpectedevidencefor van MarkenLichtenbeltWD,Vanhommerig JW, SmuldersNM, Virtanen KA,LidellME,OravaJ,HeglindM,Westergren R,NiemiT, Cypess AM,LehmanS,Williams G,Tal I,RodmanD,GoldfineAB, 1518–1525. (doi:10.1016/j.cmet.2015.09.007) (doi:10.1056/NEJMoa0808949) 2009 Physiological Reviews 2009 360 New England Journal ofMedicine New EnglandJournal Frontiers inEndocrinology 1509–1517. 360 M Chondronikolaandothers et al 2007 1500–1508. . Identificationand Cell Metabolism et al American Journal of American Journal 293 2004 . Functionalbrown (doi:10.1056/ E444–E452. 84 New (doi:10.1056/ 277–359.
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