Differences in the metabolic status of healthy adults with and without active brown adipose tissue

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1 Wien Klin Wochenschr (2013) 125: DOI /s Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue Qiongyue Zhng Hongying Ye Qing Mio Zhoyun Zhng Yi Wng Xioming Zhu Shuo Zhng Chunto Zuo Zhengwei Zhng Zhemin Hung Ruidn Xue Meifng Zeng Hiyn Hung Wnzhu Jin Qiqun Tng Yihui Gun Yiming Li Received: 1 My 2013 / Accepted: 13 September 2013 / Published online: 22 October 2013 Springer-Verlg Wien 2013 Summry Bckground Previous studies hve proven the existence of ctive brown dipose tissue (BAT) in dults; however, its effect on systemtic metbolism remins uncler. Aim The current study ws designed to investigte the differences in the metbolic profiles of helthy dults with nd without ctive BAT using positron emission tomogrphy computed tomogrphy (PET-CT) scns in the un-stimulted stte. Methods A cross-sectionl nlysis ws performed to ssess the helth of dults using PET-CT whole-body scns t Hushn Hospitl Medicl Centre between November 2009 nd My A totl of 62 helthy dults with ctive BAT were enrolled in the BAT-positive group. For ech positive subject, sme-gender individul who underwent PET-CT the sme dy nd who hd no detectble BAT ws chosen s the negtive control. Y. Li ( ) Q. Zhng H. Ye Q. Mio Z. Zhng Y. Wng X. Zhu S. Zhng R. Xue M. Zeng Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Hushn Hospitl, Fudn University, 12 Wulumuqi Middle Rod, Shnghi , Chin e-mil: yimingli.fudn@gmil.com Y. Gun C. Zuo Z. Zhng Z. Hung PET Center, Division of Nucler Medicine, Hushn Hospitl, Fudn University, 518 Wuzhong Est Rod, Shnghi , Chin e-mil: gunyihui@hotmil.com H. Hung Q. Tng The Key Lbortory of Moleculr Medicine, Ministry of Eduction nd Institute of Biomedicl Sciences, Shnghi Medicl College, Fudn University, Shnghi, Chin W. Jin The Key Lbortory of Animl Ecology nd Conservtion Biology, Institute of Zoology, Chinese Acdemy of Sciences, Beijing, Chin Body composition ws mesured, nd blood smples were collected for ssys of metbolic profiles nd other biomrkers. Results In both the mle nd femle groups, BAT-positive individuls were younger nd hd lower body mss indexes, fsting insulin, insulin resistnce, nd leptin, but greter level of high-density lipoprotein cholesterol compred with the negtive controls. In the mle group, body ft content nd levels of tumor necrosis fctor-α were significntly lower in the BAT-positive thn in the negtive control group. Conclusions The helthy dults with ctive BAT in n un-stimulted stte hd fvorble metbolic profiles suggesting tht ctive BAT my be potentil trget for preventing nd treting obesity nd other metbolic disorders. Keywords Brown dipose tissue Humn Metbolism High-density lipoprotein cholesterol Unterschiede im Stoffwechselsttus gesunder Erwchsener mit und ohne ktivem brunem Fettgewebe Zusmmenfssung Grundlgen Frühere Studien hben die Existenz von ktivem brunem Fettgewebe (BAT) bei Erwchsenen nchgewiesen. Die Wirkung dieses Gewebes uf den systemischen Stoffwechsel bleibt llerdings unklr. Ziel Die vorliegende Studie plnte zu erforschen, ob ein Unterschied in den Stoffwechselprofilen gesunder Erwchsener mit beziehungsweise ohne BAT besteht, wobei PET-CT Scns im nicht stimulierten Zustnd verwendet wurden. Methodik Am Hushn Hospitl Medicl Center wurde zwischen November 2009 und Mi 2010 eine horizontle Anlyse durchgeführt, um die Gesundheit von Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue 687

2 Erwchsenen zu erfssen, wobei PET-CT Gnzkörper Scns zur Verwendung gelngten. Insgesmt wurden 62 gesunde Erwchsene mit ktivem BAT in die BAT positive Gruppe ufgenommen. Für jede positiv getestete Person wurde ls negtive Kontrolle eine Person gleichen Geschlechts usgewählt, die m selben Tg eine PET-CT Untersuchung htte und bei der kein ktives BAT nchgewiesen werden konnte. Die Körperzusmmensetzung wurde gemessen und Blutproben zur Bestimmung von Stoffwechselprofilen und nderer Bio-Mrker wurden bgenommen. Ergebnisse Sowohl die männlichen ls uch die weiblichen BAT positiven Individuen wren jünger und htten einen geringeren BMI, ein niedrigeres Nüchtern-Insulin, niedrigere Insulinresistenz und Leptin. Nur ds HDL-Cholesterin wr im Vergleich zur BAT negtiven Gruppe erhöht. Bei den BAT positiven Männern wr der Körperfettgehlt und die Konzentrtion von Tumornekrosefktor-lph (TNF lph) signifiknt niedriger ls bei den BAT negtiven Kontrollen. Schlussfolgerungen Die gesunden Erwchsenen mit ktivem BAT htten im nicht-stimulierten Zustnd ein günstigeres Stoffwechselprofil. Dies legt nhe, dss ds ktive BAT ein mögliches Zielorgn bei der Vorbeugung und Behndlung der Adiposits und nderer Stoffwechselerkrnkungen sein könnte. Schlüsselwörter Brunes Fettgewebe (BAT) Humner Metbolismus Stoffwechselprofil HDL-Cholesterin Abbrevitions BAT Brown dipose tissue PET-CT Positron emission tomogrphy computed tomogrphy BMI Body mss index HDL-c High-density lipoprotein cholesterol LDL-c Low-density lipoprotein cholesterol TNF-α Tumor necrosis fctor-α SUV Stndrd uptke vlue FDG Fluorodeoxyglucose WHR Wist hip rtio HOMA-IR Homeosttic model of ssessment insulin resistnce FABP4 Free ftty cid-binding protein-4 UCP1 Uncoupling protein 1 MET Metbolic equivlent Introduction Brown dipose tissue (BAT) plys n importnt role in the thermogenesis nd homeostsis of energy metbolism [1]. Active BAT, with high stndrd uptke vlue (SUV), hs been shown by positron emission tomogrphy computed tomogrphy (PET-CT) scns in dults, confirmed by biopsy, nd proven by severl independent studies [2 4]. In the un-stimulted stte, the generl prevlence of BAT detected by PET-CT vries from %, but cn be incresed to pproximtely 95.8 % (23 of 24) when triggered by cold stress (16 C) for 2 h [2]. In ddition, the uptke of fluorodeoxyglucose (FDG) by BAT cn be inhibited by het, specil medicines such s proprnolol, or high-ft diet [5, 6]. Retrospective studies, bsed minly on ptients with tumors, hve shown tht the probbility of the detection of BAT is inversely correlted with ge, outdoor temperture, nd body mss index (BMI) [3]. In 2009, Sito et l. [7] found tht the mount of BAT quntified in the neck re ws inversely correlted with BMI nd ft mss. In 2009, Vn Mrken Lichtenbelt et l. [2] lso found tht BAT ctivity under cold stress ws negtively correlted with the percentge of body ft nd positively correlted with resting metbolic rte. These results suggested tht ctive BAT in dults my be beneficil to systemic metbolism, nd tht triggering BAT ctivity or enhncing the formtion of BAT might be nother useful strtegy for fighting obesity nd obesity-relted disorders. However, the potentil differences in the metbolic profiles of helthy dults with nd without ctive BAT in n un-stimulted stte hve not been investigted. In this cross-sectionl study, the differences of systemic metbolic profiles were compred between helthy dults with nd without ctive BAT detected by PET-CT in un-stimulted stte. Methods Reserch design nd procedure In Chin, some individuls undergo PET-CT scn in some clinic centers to screen for tumor for helth ssessment. In this rticle, these helthy dults were recruited into the cross-sectionl nlysis just for helth ssessment in the medicl exmintion center (PET-CT center in Hushn Hospitl) t their own expenses, who lso volunteered for scientific study nd signed written consents between November 2009 nd My All subjects were 18 yers of ge; hd no history of obesity, dibetes, hert disese, severe infection, chronic liver or kidney disese, or cncer; nd did not tke ny regulr medictions. Procedure of the study is shown in Fig. 1. A totl of 62 dults with ctive BAT, detected by PET- CT scn, were recruited s the BAT-positive group. For ech BAT-positive subject, negtive control subject ws chosen. To minimize possible interferences such s due to ge, gender, or outdoor temperture, the negtive control subject ws of the sme gender, ws of the closest ge possible to the positive individul, nd underwent the scns on the sme dy. The ethics committee of Hushn Hospitl t Fudn University pproved the study, nd written consent ws obtined from ll volunteers. The tril ws registered t Clinicl- Trils.gov (NCT ). 688 Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue

3 Fig. 1 Reserch design nd procedure PET-CT scn In this study, the quntifiction of the ctivity of BAT in regions of interest, which included the principl cervicl, suprclviculr, prvertebrl, xillry, nd superior medistinl depots of BAT, ws performed. Room temperture in the PET-CT center (31 12 N, E) ws mintined t C. All subjects styed in the room t lest for 1 h before the injection of [ 18 F]FDG t dose of MBq/kg through the cubitl vein, nd they underwent PET-CT scn only one time. One hour fter the injection, the whole-body imges were cquired with Biogrph 64 PET-CT scnners (SIEMENS, Germny). The CT scn time for the body ws 2 min per bed position. Five or six bed positions per subject were needed to cover the res where BAT is usully found. The resulting totl verge dose of rdition from the low-dose CT scn nd the injected rdioctive trcer ws pproximtely 10.5 mci. Clcultions were completed with OpenPACS nd PET-CT Viewer softwre ( edu/jpnm/displyfreewre/) [8]. The dipose tissue ws identified by CT ( 250 to 50 Hounsfield units), nd PET determined the uptke of [ 18 F]FDG. Ares of dipose tissue lrger thn 4 mm in dimeter nd with the mximum [ 18 F]FDG SUV (SUV mx) of 2.0 were identified s the ctive BAT regions [3]. The exmple of two PET-CT imges of subjects with nd without ctive BAT is shown in Fig. 2. Other dt collection Medicl, smoking, nd drinking histories, s well s exercise hbits, height, weight, hert rte, nd systolic blood pressure (SBP)/distolic blood pressure (DBP), were collected from subjects before scnning, by the stndrd opertion protocol. According to the type, the weekly frequency, nd the durtion of physicl ctivities, the level of exercise ws quntified syntheticlly. The level of exercise ws clssified by the respective metbolic equivlent (MET) vlue ( Yes represented moderte or vigorous intensity of exercise 3 METs, No represented light intensity of exercise < 3 METs) [9, 10]. Totl percentge of ft content ws mesured vi the body composition nlyzer (TANITA, TBF-300A, Jpn). Wist circumference ws mesured t the minimum circumference between the ilic crest nd the rib cge, nd hip circumference ws mesured round the mximum protubernce of the buttocks. Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue 689

4 Fig. 2 The imges of subjects with nd without ctive brown dipose tissue ssessed by PET-CT with [18F]FDG. The imge shows extended BAT uptke of [ 18 F]FDG in neck, suprclviculr, xillry, medistinl, nd prvertebrl regions in helthy dult. b The imge of the other subject in whom PET-CT ws performed in the sme dy shows no BAT uptke of [ 18 F]FDG in the sme regions Mesurements of blood smples In this rticle, the blood smples of subjects were drwn in the fsting stte (t lest fter n 8-h fst), just before the PET-CT scn. Plsm glucose nd lipid levels were mesured using n utomtic biochemicl nlyzer (Hitchi 7600, Jpn). Plsm insulin concentrtion ws mesured by rdioimmunossy (SIEMENS, ADVIA Centur XP). Plsm estrdiol nd testosterone levels were mesured by electrochemiluminescence immunossy (Roche, MODULAR E170). Enzyme-linked immunosorbent ssy kits were used to mesure concentrtions of leptin, diponectin (Mercodi, Sweden), free ftty cidbinding protein-4 (FABP4; Biovendor, Czech Republic), nd tumor necrosis fctor-α (TNF-α; Anogen, Cnd), ccording to the mnufcturers instructions. Sttisticl nlysis All nlyses were performed using the softwre SPSS (version 13.0). Strtified by gender, continuous vribles were presented s mens nd stndrd devitions if normlly distributed or s medins nd interqurtile rnges if symmetriclly distributed. Differences in the chrcteristics between the BAT-positive nd BATnegtive groups were ssessed using the Student s t test for normlly distributed quntittive vribles or the Mnn Whitney U test for symmetriclly distributed quntittive vribles. The functions of ge, BMI, smoking history, drinking history, nd exercise s predictors of ctive BAT were tested by logistic regression using univrite nd multivrite models. Odds rtios nd 95 % confidence intervls were estimted s mesures of the mgnitude of the ssocitions. Multiple liner regression nlysis ws performed to exmine the ssocitions between ctive BAT nd vrious metbolic indexes. All p-vlues presented re two-tiled, nd vlues < 0.05 re considered to be sttisticlly significnt. Results Clinicl chrcteristics The prevlence of ctive BAT in this group ws 3.15 % (79/2506). A totl of 17 BAT-positive individuls were excluded due to filure to obtin written consent or to find negtive control. Consequently, 62 pirs of subjects were recruited for this study (22 pirs mle, 40 pirs femle). In both mle nd femle groups, BAT-positive individuls were younger thn their controls (35.5 ± 7.8 yers vs ± 6.4 yers, p = 0.049, in the mle group; 38.0 ± 6.7 yers vs ± 7.3 yers, p = 0.001, in the femle group), nd the BAT-positive group hd lower BMI (21.3 ± 2.5 kg/m 2 vs ± 4.3 kg/m 2, p = 0.004, in the mle group; 21.3 ± 2.2 kg/m 2 vs ± 2.5 kg/m 2, p = 0.026, in the femle group; Tble 1). Compred with their negtive controls, the BAT-positive mles hd lower wist hip rtio (WHR; 0.9 ± 0.1 vs. 0.9 ± 0.1, p = 0.020). SBP/DBP nd hert rte were not significntly different between the BAT-positive nd BAT-negtive groups. Body composition None of the recruited subjects were obese [BMI > 30 kg/m 2 ccording to the 2005 World Helth Orgniztion criteri]. In the mle group, BAT-positive subjects hd significntly lower ft percentge thn the negtive controls (19.5 ± 5.9% vs ± 4.4 %, p < 0.001; Tble 1). However, this ws not seen in the femle group. Lipid profiles In both mle nd femle groups, in contrst to negtive controls, the level of high-density lipoprotein cholesterol (HDL-c) ws significntly higher in BAT-positive subjects (1.6 ± 0.3 mmol/l vs. 1.1 ± 0.2 mmol/l nd 2.0 ± 0.5 mmol/l vs. 1.5 ± 0.3 mmol/l, p < 0.001, in both mle nd femle 690 Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue

5 Tble 1 Chrcteristics of the subjects nd body composition Vrible BAT positive BAT negtive p-vlue Mle (N = 22) Clinicl chrcteristics Age (yers) 35.5 ± ± SBP (mmhg) ± ± DBP (mmhg) 77.1 ± ± Hert rte (bets/min) 74.1 ± ± Body composition BMI (kg/m 2 ) 21.3 ± ± Wist circumference (cm) 78.2 ± ± 9.7 < WHR 0.9 ± ± Body ft (%) 19.5 ± ± 4.4 < Femle (N = 40) Clinicl chrcteristics Age (yers) 38.0 ± ± SBP (mmhg) ± ± DBP (mmhg) 78.7 ± ± Hert rte (bets/min) 74.2 ± ± Body composition BMI (kg/m 2 ) 21.3 ± ± Wist circumference (cm) 76.3 ± ± WHR 0.8 ± ± Body ft (%) 29.3 ± ± SBP systolic blood pressure, DBP distolic blood pressure Vlues re presented s mens ± stndrd devitions; BMI (body mss index) is the weight in kilogrms divided by the squre of the height in meters; nd WHR (wist-to-hip rtio) is the wist circumference in centimeters divided by the hip circumference in centimeters groups, respectively; Tble 2). The levels of totl cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), nd triglycerides (TGs) were not significntly different between BAT-positive nd BAT-negtive subjects. However, the TC-to-HDL rtio (TC/HDL) ws significntly lower in BAT-positive popultions thn in negtive controls (3.1 ± 0.7 vs. 4.5 ± 1.2 nd 2.7 ± 0.5 vs. 3.4 ± 0.8, p < 0.001, in both mle nd femle groups, respectively; Tble 2). Fsting glucose nd insulin Compred with their negtive controls, the BAT-positive mles hd significntly lower fsting glucose (4.7 ± 0.4 mmol/l vs. 5.0 ± 0.6 mmol/l, p = 0.029) nd fsting insulin levels [20.2 ( ) pmol/l vs ( ) pmol/l, p = 0.026]. However, in the femle groups, only the fsting insulin level of the BAT-positive subjects ws significntly lower thn tht of negtive controls [20.1 ( ) pmol/l vs ( ) pmol/l, p = 0.006], wheres the fsting plsm glucose levels showed no difference (Tble 2). The homeosttic model of ssessment insulin resistnce (HOMA-IR) in the BAT-positive Tble 2 Metbolic vribles of the subjects Vrible BAT positive BAT negtive p-vlue Mle (N = 22) Lipid levels (mmol/l) Totl cholesterol 4.9 ± ± LDL cholesterol 2.9 ± ± HDL cholesterol 1.6 ± ± 0.2 < Triglycerides 1.1 ( ) 1.3 ( ) TC/HDL b 3.1 ± ± 1.2 < Glucose metbolism FPG (mmol/l) 4.7 ± ± Fsting insulin (pmol/l) c 20.2 ( ) 39.7 ( ) HOMA-IR d 0.7 ( ) 1.64 ( ) Femle (N = 40) Lipid levels (mmol/l) Totl cholesterol 5.1 ± ± LDL cholesterol 2.8 ± ± HDL cholesterol 2.0 ± ± 0.3 < Triglycerides 0.9 ( ) 0.8 ( ) TC/HDL b 2.7 ± ± 0.8 < Glucose metbolism FPG (mmol/l) 4.8 ± ± Fsting insulin (pmol/l) c 20.1 ( ) 29.9 ( ) HOMA-IR d 0.7 ( ) 1.1 ( ) LDL low-density lipoprotein, FPG fsting plsm glucose Vlues re presented s mens ± stndrd devitions if normlly distributed or s medins (interqurtile rnges) if symmetriclly distributed b TC/HDL is the totl cholesterol divided by the high-density lipoprotein c Vlues for insulin were converted to picomole per liter by multiplying by 6.0 d HOMA-IR (homeostsis model of ssessment insulin resistnce) ws clculted using the following formul: the fsting glucose in millimoles per liter multiplied by fsting insulin in microunit per milliliter nd divided by 22.5 groups ws significntly lower thn tht of the negtive controls (0.7 vs. 1.6, p = 0.016, in the mle group; 0.7 vs. 1.1, p = 0.005, in the femle group; Tble 2). Adipokines nd other biochemicl mrkers Leptin levels were significntly lower in both mle nd femle BAT-positive individuls thn in their negtive controls [1.4 ( ) ng/ml vs. 4.8 ( ) ng/ml, p < 0.001, in the mle group; 7.9 ± 4.8 ng/ml vs ± 6.6 ng/ml, p = 0.008, in the femle group; Tble 3]. However, diponectin nd FABP4 levels showed no significnt difference. In the mle group, the level of TNF-α ws significntly lower in BAT-positive individuls thn in the negtive controls [11.7 ( ) pg/ml vs ( ) pg/ml, p < 0.001]. However, in the femle group, there ws no such difference between the BAT-positive individuls nd their negtive controls. Due to differences in the prevlence of BAT between femles nd mles [2], we investigted the levels of serum Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue 691

6 Tble 3 Adipokines nd other biochemicl mrkers of the subjects Vrible BAT positive BAT negtive p-vlue Mle (N = 22) Leptin (ng/ml) 1.4 ( ) 4.8 ( ) < Adiponectin (µg/ml) 8.1 ± ± FABP4 (ng/ml) 9.8 ± ± TNF-α (pg/ml) 11.7 ( ) 16.0 ( ) < Testosterone 15.3 ± ± (nmol/l) Femle (N = 40) Leptin (ng/ml) 7.9 ± ± Adiponectin (µg/ml) 8.9 ± ± FABP4 (ng/ml) 11.4 ± ± TNF-α (pg/ml) 13.4 ( ) 14.9 ( ) Estrdiol (pmol/l) ( ) ( ) BAT brown dipose tissue, TNF- tumor necrosis fctor-, FABP4 free ftty cid-binding protein-4 Vlues re presented s mens ± stndrd devitions if normlly distributed or s medins (interqurtile rnges) if symmetriclly distributed testosterone nd estrdiol to observe the reltionship between BAT nd these sex hormones. We found tht, in mle group, the testosterone levels were not significntly different between the BAT-positive subjects nd the negtive controls. Similrly, in femle group, the estrdiol levels were lso not significntly different (Tble 3). Multiple liner regression models were performed to investigte the possible ssocitions of ctive BAT with vrious metbolic indexes, nd to elucidte the differences between the mle nd femle groups. After djusting for ge, BMI, nd body ft percentge, the levels of HDL, TC/HDL, nd leptin remined significntly different between the BAT-positive nd BAT-negtive groups (p < , p < 0.005, p < 0.05, respectively; Tble 4). Predictors of ctive brown dipose tissue Becuse the gender nd dte of PET-CT scn in two groups were mtched, the gender nd outdoor temperture were not considered s predictors. In univrite nlyses, BAT ws more frequently detected in young subjects (p = 0.001), slender individuls (p = 0.002), nd those who hd exercised more often (p = 0.005; Tble 5). In multivrite nlyses, two predictors (ge nd exercise) remined significnt. Thus, BAT ws found most frequently in young subjects (p = 0.002) nd in individuls who prticipted more in exercise nd sports (p = 0.002; Tble 5). Discussion PET-CT hs long been used to detect mlignnt tissue. Moreover, it is often used for medicl check-ups in some clinic centers worldwide. In Chin, some individuls undergo PET-CT scn only for helth ssessment. This Tble 4 Multiple liner regression models were performed for ssocitions of ctive BAT with vrious metbolic indexes Vrible Model Mle Femle β SE P β SE P Lg (HOMA IR) b FBG Lg (insulin) b TC Lg (TG) b HDL < < < < < < LDL TC/HDL Lg < (letpin) b < < Adiponectin FABP Lg (TNF-α) b WHR Ft % HOMA-IR homeostsis model of ssessment insulin resistnce, FBG fsting blood glucose, TC totl cholesterol, TG trigliceride, HDL high-density lipoprotein, LDL low-density lipoprotein, FABP4 free ftty cid-binding protein-4, TNF- tumor necrosis fctor-, WHR wist hip rtio Vlues of β re regression coefficients: model 1, fter djustment for ge; model 2, fter djustment for ge nd body mss index; model 3, fter further djustment for ft percentge b Logrithmic trnsformtion ws used to trnsform dt to norml distribution, nd described s Lg (X) insted of X 692 Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue

7 Tble 5 Predictors of ctive brown dipose tissue bsed on positron emission tomogrphy computed tomogrphy scnning Vrible Univrite nlysis Multivrite nlysis Odds rtio (95% CI) p-vlue Odds rtio (95% CI) p-vlue Age (+ 10 yers) 0.4 ( ) ( ) BMI (+ 1 kg/m 2 ) 0.8 ( ) ( ) Smoking history (Yes vs. No) 0.9 ( ) ( ) Drinking history (Yes vs. No) 1.1 ( ) ( ) Exercise (Yes vs. No) 3.2 ( ) ( ) CI confidence intervl Age nd body mss index (BMI) re continuous vribles, nd smoking history, drinking history, nd exercise re ctegoricl vribles ws true for our cross-sectionl study exmining helthy dults in n un-stimulted stte. The current study lso used lrger smple thn previous studies [3, 4]. Our findings supports previous findings tht dults with ctive BAT re younger nd hve lower BMI thn those without ctive BAT [3, 11, 12]. Compred with their BAT-negtive controls, the BAT-positive mles hd lower WHR nd percentge of ft mss, wheres no such difference ws found in femles. Our results suggest tht ctive BAT my be relted to body weight regultion nd ft distribution in the un-stimulted stte. Our results show, for the first time, tht dults, both mles nd femles, with ctive BAT in the un-stimulted stte hve higher level of HDL nd lower level of insulin nd HOMA-IR thn those without ctive BAT, lthough TG level is not significntly different. Metbolic disorders re often ccompnied by dyslipidemi, insulin resistnce, hyperglycemi, systemic inflmmtion, nd dipokine dysregultion [13, 14], nd the dipokines secreted from the dipose tissue re ble to ffect whole-body energy homeostsis [15]. Thus the serum TNF-α, leptin, nd diponectin levels were lso investigted in the current study. The BAT-positive group hd significntly lower level of leptin thn the BATnegtive group in both mles nd femles, nd the BATpositive mles hd significntly lower level of TNF-α thn the negtive control mles; however, no significnt difference ws found between BAT-positive nd BATnegtive femles. The reduced TNF-α nd fsting glucose levels might be secondry to lower BMI nd body ft content in mle BAT-positive group. It is well known tht TNF-α is positively ssocited with insulin resistnce nd insulin sensitivity, nd dipokines re closely ssocited with BMI nd body ft content [16 18]. The beneficil metbolic profiles in the BAT-positive group my be prtly due to lower BMI nd body ft percentge. Multiple liner regression nlyses were performed to investigte the possible ssocitions of ctive BAT with vrious metbolic indexes, nd to elucidte the differences between the mle nd femle groups. After djusting for ge, BMI, nd the body ft percentge, only HDL levels, TC/HDL, nd leptin levels remined significntly different between the BAT-positive nd BAT-negtive groups. Recently Brtelt et l. [19] demonstrted tht coldinduced ctivtion of BAT in mice leds to significnt reduction in circulting TG levels s result of incresed uptke of TG by BAT nd slight elevtion of HDL levels likely due to n increse in TG-rich lipoprotein-derived HDL precursors. In humns, Vn Mrken Lichtenbelt et l. [2] exmined the presence nd ctivity of BAT in helthy volunteers nd its reltion to body composition nd energy expenditure under both thermoneutrl (22 C) nd mild cold exposure (16 C) conditions; however, chnges in lipid profiles long with the coldinduced ctivtion of BAT were not investigted. Our study found significnt nd independent difference in HDL levels nd TC/HDL long with ctive BAT fter djusting for BMI nd ft percentge. HDL is wellknown protective fctor for crdiovsculr disese, nd Europen prospective study showed tht elevted TC/ HDL rtios re directly relted to the incidence of coronry hert disese, nd re independent of ny other single lipid bnormlity [20]. Our results found tht dults with ctive BAT in n un-stimulted stte hd higher levels of HDL, lthough the possible mechnisms nd the potentil clinicl significnce need further investigtion. Leptin is one of the most importnt circulting dipokines. Minly secreted from white dipose tissue, it regultes body weight by decresing ppetite nd incresing sympthetic nerve ctivity in mice, which increses energy expenditure in BAT [21, 22]. Studies in nimls nd humns show tht the circulting leptin level is proportionl to BMI nd ft mss [22]. Most of these studies focused on the effects of centrl or intrvenous leptin dministrtion on the ctivity of BAT nd the expression of leptin in BAT [23, 24]. Results in rodents show tht leptin cn increse the ctivity of BAT [25]. In 2001, Mrgreto et l. [22] found significnt positive ssocition between the interscpulr BAT uncoupling protein 1 (UCP1) nd serum leptin levels. However, in 2006, Wng et l. [26] found tht serum leptin levels were positively correlted with body mss nd body ft mss, but negtively correlted with the UCP1 protein content of BAT in voles. Our study reported, for the first time, the difference in serum leptin levels between dults with nd without ctive BAT in n un-stimulted stte. Serum leptin level ws lower in the BAT-positive group thn in the BAT-negtive group, wheres the BAT-positive group hd lower BMI nd ft percentge thn the negtive control group. After djusting for the BMI nd ft percentge, serum leptin levels remined different in the BAT-positive vs. Differences in the metbolic sttus of helthy dults with nd without ctive brown dipose tissue 693

8 BAT-negtive group, suggesting tht BAT ctivity my directly ffect circulting leptin levels. In 1998, Cncello et l. [27] found tht in brown dipocytes of wrm-cclimted mice, leptin mrna nd protein expression ws higher t 28 C thn t 19 C, wheres the chnge of UCP1 expression ws opposite. In 2008, Korc et l. [28] found tht the leptin expression in BAT ws suppressed in cold-cclimted rts compred with room temperturecclimted rts. These findings in nimls re consistent with those found in humns. Therefore, the lower level of serum leptin in dults with ctive BAT my be ttributed to the lower BMI nd ft mss s well s its decresed expression in ctive BAT. In 2009, Cypess et l. [3] performed retrospective study indicting tht the probbility of the detection of BAT ws inversely correlted with BMI, ge, outdoor temperture, nd bet-blocker usge. In the current study, the reltionship between BAT nd living hbits ws lso ddressed. Univrite nlysis showed n inverse correltion between the prevlence of detectble BAT nd ge nd direct correltion between BAT nd exercise; fter multivrite nlysis, this correltion persisted. These results suggest tht ctive BAT my protect ginst gerelted metbolic disorders [29]. Furthermore, our study suggests tht exercise my rise the ctivity of BAT. Previous studies done in nimls showed tht exercise trining potentited BAT thermogenesis, which reduced the body weight in OVX obese rts [30]. Recently, new hormone, irisin, ws discovered in nother study in nimls. In tht study, this hormone improved with exercise nd stimulted UCP1 expression s well s brod progrm of brown-ft-like development [31]. Thus, pproches for incresing BAT mss nd/or stimulting its ctivity, such s incresed physicl ctivity, my promote metbolism. There re certin limittions in the current study. Due to methodologicl constrints, quntifiction of BAT ctivity nd further nlysis of the correltions between BAT ctivity nd other fctors were not performed. Insulin sensitivity ws evluted by HOMA-IR insted of the gold stndrd clmp. In summry, our results indicte tht helthy dults with ctive BAT in n un-stimulted stte hve fvorble metbolic sttus, especilly with higher level of HDL nd lower level of leptin, which is independent of other fctors. Active BAT might be cndidte for improving metbolic conditions in humns, thus providing new therpeutic trget for combting obesity, dibetes, hyperlipidemi, nd other metbolic disorders. Grnt support This study ws supported by grnts (No.10JC , No.11PJ ) from the Shnghi Committee of Science nd Technology, Chin, (No , No nd No ) from the Ntionl Nturl Science Foundtion of Chin, (No.XYQ ) from the Shnghi Municipl Helth Bureu, (No.09FQ71) from the Young Science Fund of Fudn University, (No ) from the Institutes of Biomedicl Sciences of Fudn University, (No.EYF151063) from the Grdute Innovtion Fund of Fudn University, (No.2011CB910201) from the Ntionl Bsic Reserch Progrm of Chin (973 Progrm), nd (No.985III-YFX0302) from the 985 Project. Acknowledgments The uthors thnk the stff of PET Center (Hushn Hospitl) for their help in performing the study, the stff from Division of Endocrinology nd Metbolism nd the Center of Lbortory Medicine (Hushn Hospitl) for their technicl ssistnce, nd the subjects for their prticiption in the study. Conflict of interest No potentil conflicts of interest relevnt to this rticle were reported. References 1. Rothwell NJ, Stock MJ. 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