Kirsi A. Virtanen, M.D., Ph.D., Martin E. Lidell, Ph.D., Janne Orava, B.S., Mikael Heglind, M.S., Rickard Westergren, M.S., Tarja Niemi, M.D., Markku Taittonen, M.D., Ph.D., Jukka Laine, M.D., Ph.D., Nina-Johanna Savisto, M.S., Sven Enerbäck, M.D., Ph.D., and Pirjo Nuutila, M.D., Ph.D.
Using positron-emission tomography (PET), we found that cold-inducedglucose uptake was increased by a factor of 15 in paracervicaland supraclavicular adipose tissue in five healthy subjects.We obtained biopsy specimens of this tissue from the first threeconsecutive subjects and documented messenger RNA (mRNA) andprotein levels of the brown-adipocyte marker, uncoupling protein1 (UCP1). Together with morphologic assessment, which showednumerous multilocular, intracellular lipid droplets, and withthe results of biochemical analysis, these findings documentthe presence of substantial amounts of metabolically activebrown adipose tissue in healthy adult humans.
Active brown adipose tissue helps maintain normal body temperaturein newborn infants. It is believed that this tissue regresseswith increasing age and is completely lost by the time a personreaches adulthood.1 However, the capacity to produce brown adiposetissue in adulthood has been shown in patients with catecholamine-secretingtumors such as pheochromocytomas and paragangliomas, in whomdistinct brown-adipose-tissue depots develop.2,3 When scanningwith a combination of PET and computed tomography (CT) —with the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) asa tracer — is used in the diagnosis of neoplasms and theirmetastases, the results can be confounded by a high glucoseuptake in the supraclavicular tissue; this increased glucoseuptake has been thought to represent the presence of brown adiposetissue.4 This view has been supported by the localization ofthe 18F-FDG in adipose tissue on CT images5 and its sensitivityto propranolol6 and to environmental temperature before PETscanning7; furthermore, this phenomenon occurs more often duringthe cold winter months than in the summertime.8 However, toour knowledge and as has been noted in a recent review,9 thereare no direct data that clearly show that tissue from theseareas of cold-induced 18F-FDG uptake in healthy adult subjectsindeed has histologic features of brown adipose tissue and expressesmRNA and proteins that distinguish it from white adipose tissue.This is an important point, since such data would be necessaryto identify bona fide brown adipose tissue in healthy adultsand to indicate that such tissue is part of normal human physiologyafter infancy.
Methods
Subjects
We studied a group of five healthy volunteers, all of whom providedwritten informed consent. The study protocol was reviewed andapproved by the ethics committee of the Hospital District ofSouthwest Finland. The study was conducted according to theprinciples of the Declaration of Helsinki. Subjects were recruitedthrough advertisements in the local newspaper. All potentialsubjects were screened for metabolic status, and only thosewith normal glucose tolerance and normal cardiovascular status(as assessed on the basis of electrocardiograms and measuredblood pressure) were included. Subjects had to be 20 to 50 yearsof age.
Study Design
Each of the five subjects underwent two PET–CT (with 18F-FDG)studies, one of which was performed during cold exposure andthe other during warm conditions. Before being positioned inthe scanner for the cold-exposure scan, the subject, while wearinglight clothing, spent 2 hours in a room that had an ambienttemperature of 17 to 19°C. While the PET–CT studywas being performed, one of the subject's feet was placed intermittentlyin ice water (5 to 9°C; 5 minutes in the water alternatingwith 5 minutes out). The scan that was obtained in warm conditionswas performed on a separate day, with the use of the same scanningprotocol as that used for the scan with cold exposure, exceptthat there was no cold exposure before the procedure and noice-water immersion of a foot during the procedure. Both scanswere obtained after the subject had fasted overnight and whilethe subject was in the supine position. Three of the volunteersprovided written informed consent for a biopsy of fat tissueto be performed; the biopsy was performed while the subjectwas under local anesthesia, and specimens of both brown andwhite adipose tissue were obtained (for further information,see the Supplementary Appendix, available with the full textof this article at NEJM.org). Measurements from the images ofactivated brown adipose tissue, as observed on the cold-exposurescans, were used as a guide for the site of the biopsy.
PET Study
The tracer 18F-FDG was synthesized in accordance with a standardoperating procedure of the Turku PET Centre, with the use ofa modified version of the method of Hamacher et al.10 Technicaldetails can be found in the Supplementary Appendix. At the beginningof the day on which the PET study was to be performed, a catheterwas inserted in the subject's antecubital vein for a bolus injectionof 18F-FDG. Another catheter was inserted in the antecubitalvein of the contralateral arm and was used to obtain samplesof venous blood during the scanning.
Biopsy Procedure
The biopsy was performed while the subject was under local anesthesia(lidocaine supplemented with epinephrine). Guided by the high-resolutionPET–CT images, a plastic surgeon collected open-biopsyspecimens from areas that corresponded to the cold-induced areasof uptake in the first three subjects (hereafter referred toas Subjects 1, 2, and 3). Immediately after removal, the tissuesample was divided into two pieces: one was fixed in formalinfor histologic examination, and the other was snap-frozen inliquid nitrogen. The frozen tissue was used for the preparationof mRNA and complementary DNA (cDNA) for use in real-time quantitativepolymerase-chain-reaction (PCR) analysis; protein was also extractedfrom the frozen tissue (see the Supplementary Appendix). Duringthe same surgical procedure, and through the same incision,an adjacent specimen of subcutaneous fat consisting of whiteadipose tissue (which served as control tissue) was obtainedfrom all three subjects and was prepared in the same way asthe specimens described above.
Microscopical Studies
We performed immunohistochemical studies using an anti-UCP1primary antibody (as described in the Supplementary Appendix),together with a horseradish peroxidase–conjugated secondaryantibody. We also performed confocal microscopy (as describedin the Supplementary Appendix).
Results
As compared with the scans obtained in warm conditions, scansobtained with cold exposure showed enhanced 18F-FDG uptake inall five subjects, most prominently in the supraclavicular area(Figure 1A, 1B, and 1C). In response to cold exposure, glucoseuptake in the supraclavicular area (as calculated with the useof graphical analysis) was higher than the uptake in adjacentwhite adipose (Figure 1D), with the mean uptake in the supraclaviculararea increased by a factor of approximately 15 (P=0.005), ascompared with an increase by a factor of 4 in the white adiposetissue (P=0.01) (Figure 1E).
Figure 1. Computed Tomographic (CT) and Positron-Emission Tomographic (PET) Images from the Neck and Upper Thoracic Region, Obtained during Cold and Warm Conditions.
Panels A, B, and C show images of the neck and upper thoracic region from Subjects 1, 2, and 3, respectively. The top row in each panel shows individual CT images, the middle row shows PET images, with the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a tracer, during cold conditions, and the bottom row shows PET images with 18F-FDG during warm conditions. The image on the left side of each row represents a transaxial slice, the image in the middle a coronal slice, and the image on the right side a sagittal slice from the region of activated brown adipose tissue. Cold-induced glucose uptake in supraclavicular tissue is marked by arrows. The color index to the left of the PET images shows the level of 18F-FDG uptake, with red indicating the highest level. Glucose uptake, calculated with the use of graphical analysis of PET data, in each of the five study subjects is shown in Panel D. Glucose uptake rates in brown adipose tissue (BAT) were assessed in the supraclavicular region, and glucose uptake rates in white adipose tissue (WAT) were assessed in the subcutaneous region corresponding to the site of the biopsies. Panel E shows a comparison of mean glucose uptake in all five subjects, calculated with the use of a paired Student's t-test. T bars indicate standard deviations.
The areas from which the open-biopsy specimens were obtainedin Subjects 1, 2, and 3 are shown by arrows in Figure 1A, 1B, and 1C,respectively. Quantitative PCR analysis of mRNA expression levelsfor multiple genes is shown in Figure 2. Assessment of the tissue-biopsyspecimens showed that expression of uncoupling protein 1 (UCP1),which is a marker gene for brown adipose tissue, was increasedby a factor of more than 1000 as compared with expression inwhite adipose tissue. UCP1 allows protons to flow back overthe mitochondrial inner membrane, generating heat instead ofATP — a process known as adaptive thermogenesis.11 Thisprocess is believed to be important for maintaining normal bodytemperature in rodents, animals that hibernate, and human newborns.12The instrumental role of UCP1 in this process has been shownin studies of mice that have a targeted deletion of this gene;these mice have a severely blunted ability to maintain normalbody temperature when they are acutely exposed to cold.13
Figure 2. Gene Expression in Brown and White Adipose Tissue.
The mean levels of expression of UCP1, DIO2, PGC1, PRDM16, and ADRB3, based on the results of quantitative real-time PCR analysis, are shown for Subjects 1, 2, and 3. Expression levels were normalized to that of β-actin and are shown as the levels in brown adipose tissue (BAT) as a multiple of the levels in white adipose tissue (WAT). T bars indicate standard deviations.
Deiodinase, iodothyronine, type II (DIO2) mRNA was also significantlyup-regulated in brown adipose tissue as compared with whiteadipose tissue in our three subjects (Figure 2). This findingis of interest because it appears that Dio2 is expressed bybrown adipocytes in order to make triiodothyronine availableto sustain the elevated metabolism of brown adipose tissue.14,15In addition, peroxisome-proliferator–activated receptor coactivator 1 (PGC1) mRNA was significantly enhanced in brownadipose tissue (Figure 2). This finding is not surprising, sincecold induction of UCP1 gene expression depends, to a large extent,on cold-induced activation of PGC1.16 Activation of PGC1 iscrucial for UCP1 induction, since deletion of PGC1 (in mice)dramatically reduces cyclic AMP–induced17 and cold-induced18activation of ucp1. The master regulator of brown-adipose-tissueformation, PR domain containing 16 (PRDM16),19 was also inducedin all three subjects (Figure 2). In mature brown adipose tissuefrom rodents, the β3-adrenergic receptor (ADRB3) is themost important of the three subtypes of β-adrenergic receptors.12We found that there was a significant induction of this receptorsubtype in brown adipose tissue as compared with white adiposetissue in the three subjects (Figure 2). The data on mRNA expressionpresented here, which are based on samples from adipose-tissuedepots identified by PET, display a gene-expression profilethat is expected for brown adipose tissue. To determine whethertissue samples corresponding to areas of cold-induced 18F-FDGuptake also expressed UCP1, the marker protein in brown adiposetissue, we performed a Western blot analysis, which showed thepresence of UCP1 protein in all three subjects, whereas thecontrol samples of white adipose tissue from these subjectsdid not express any detectable UCP1, as expected (Figure 3A).We also investigated a mitochondrial marker, cytochrome c, andfound it to be more abundant in the brown adipose tissue thanin the white adipose tissue (Figure 3B).
Figure 3. Western Blot, Histologic, and Immunofluorescence Analyses of Brown and White Adipose Tissue.
Western blots show levels of UCP1 (Panel A) and cytochrome c (Panel B) in brown adipose tissue (BAT) and white adipose tissue (WAT) from Subjects 1, 2, and 3. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a protein loading control. Sections of brown adipose tissue and white adipose tissue from Subjects 1, 2, and 3 are shown in Panel C (hematoxylin and eosin). Multilocular, intracellular lipid droplets are present in brown adipose tissue but not in white adipose tissue. Immunohistochemical staining of brown adipose tissue and white adipose tissue with a UCP1-specific antiserum (Panel D) shows that brown adipose tissue is positive for UCP1, whereas no staining is seen in white adipose tissue. Immunofluorescence staining of brown adipose tissue and white adipose tissue (Panel E) shows colocalization of UCP1 (green) and a mitochondrial marker, cytochrome oxidase subunit I (COI, orange), in brown adipose tissue. No UCP1 could be detected in mitochondria of white adipose tissue. Nuclei were stained with TO-PRO-3 (red). Scale bars represent 30 µm in Panels C and D and 5 µm in Panel E.
Histologic analysis of the biopsy samples from our three subjectsclearly showed cells with multilocular lipid droplets in thesupraclavicular depot of brown adipose tissue but not in adjacentwhite adipose tissue (Figure 3C). The results of immunohistochemicalstaining for UCP1 strengthen the indirect connection betweengene expression and histologic features, since the brown adiposetissue had substantial levels of UCP1, whereas the white adiposetissue did not (Figure 3D). Laser confocal microscopy also showedthat in brown adipose tissue, the UCP1 signal colocalized withthe signal for a mitochondrial marker (cytochrome oxidase subunitI), resulting in an overlay that indicated nearly perfect colocalization(Figure 3E; see also the Supplementary Appendix). There wasno detectable UCP1 in white-adipose-tissue sections (Figure 3E).
Discussion
Both the PET–CT studies and the studies of tissue-biopsyspecimens indicate that normal adult humans have brown adiposetissue. Brown adipose tissue expresses substantial amounts ofUCP1 protein; it also contains more cytochrome c than whiteadipose tissue, as one would expect, since human brown adiposetissue is mitochondria-dense, in contrast to white adipose tissue,which has relatively few mitochondria.
On the basis of the data presented here and previous findingsregarding the metabolism of brown adipose tissue, we speculatethat activation of brown adipose tissue by cold exposure maybe important in terms of energy expenditure in humans. For example,on the basis of data derived from the PET–CT scans inone of our subjects, the weight of the supraclavicular brown-adipose-tissuedepot (both sides included) was 63 g. The rate of glucose uptakewas 12.2 µmol per 100 g per minute, which is equivalentto 7.7 µmol for the entire depot. During a 24-hour activationperiod, 11 mmol of glucose would have been taken up by the brown-adipose-tissuedepot. Since the substrate for activated brown adipose tissueconsists predominantly of fatty acids, this finding may be important.In fact, during activation of brown adipose tissue, only approximately10% of the total metabolism of brown adipose tissue is derivedfrom glucose uptake.20 Thus, if the brown adipose tissue inthis example were fully activated, it would burn an amount ofenergy equivalent to approximately 4.1 kg of adipose tissueover the course of a year. We believe that this is a modestassumption, since the degree of activation of brown adiposetissue most likely is submaximal (we estimate it to be 50%).Furthermore, studies in rodent models indicate that the contributionof glucose to the metabolism of fully activated brown adiposetissue is an estimated 2% at maximal stimulation.20 On the basisof this example, we speculate that in humans, activated brownadipose tissue has the potential to contribute substantiallyto energy expenditure.
In conclusion, our studies in healthy subjects show that cold-inducedglucose uptake in supraclavicular adipose-tissue depots is increasedby a factor of 15 and that this tissue expresses mRNA for markersof brown adipose tissue — namely UCP1, DIO2, PGC1, PRDM16,and ADRB3. In addition, the tissue expresses substantial levelsof UCP1 protein and cytochrome c, as assessed by Western blotanalysis, and is characterized morphologically by multilocular,intracellular lipid droplets. Finally, the tissue shows mitochondriallocalization of the UCP1 protein. In our opinion, these findingsconstitute direct identification of functional human brown adiposetissue. On the basis of these biochemical, molecular, and morphologiccriteria, we believe that brown adipose tissue is present inhealthy adults. We suggest that the presence of brown adiposetissue in normal adults is worthy of further study and speculatethat this tissue might provide a pharmacologic target, giventhe current obesity pandemic.
Supported by grants from the Swedish Research Council (K2005-32BI-15324-01A),the European Union (QLK3-CT-2002-02149, DIABESITY, and LSHM-CT-2003-503041),the Arne and Inga Britt Foundation, the Söderberg Foundation,the Swedish Foundation for Strategic Research through the Centerfor Cardiovascular and Metabolic Research, the Academy of Finland,the University of Turku, Turku University Hospital, and ÅboAcademy and by a contract with the European Commission (LSHMCT-2005-018734).
No potential conflict of interest relevant to this article wasreported.
We thank Gunilla Petersson and the staff of Turku PET Centerfor technical assistance.
Source Information
From the Turku PET Center, University of Turku (K.A.V., J.O., N.-J.S., P.N.); and the Departments of Surgery (T.N.), Anesthesiology (M.T.), Pathology (J.L.), and Medicine (P.N.), Turku University Hospital — both in Turku, Finland; and the Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden (M.E.L., M.H., R.W., S.E.). Drs. Virtanen and Lidell contributed equally to this article. This article (10.1056/NEJMoa0808949) was last updated on September 9, 2009, at NEJM.org.
Address reprint requests to Dr. Enerbäck at the Department of Medical and Clinical Genetics, P.O. Box 440, University of Göteborg, SE 405 30 Göteborg, Sweden, or at sven.enerback{at}medgen.gu.se.
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The Importance of Brown Adipose Tissue
Timmons J. A., Pedersen B. K., Stefan N., Pfannenberg C., Häring H.-U., Villarroya F., Domingo P., Giralt M., Jacene H. A., Wahl R. L., Lee P., Ho K. K.Y., Fulham M. J., Sacks H. S., van Marken Lichtenbelt W. D., Schrauwen P., Teule G.J. J., Cypess A. M., Kahn C. R., Enerbäck S., Oksi J., Nuutila P.
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A correction has been published: N Engl J Med 2009;361(11):1123.
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