Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

Introduction

Since the earliest observations describing a gland-like adipose tissue, there has been a fascinating mystique around the tissue we now recognize as brown adipose tissue (BAT). Originally referred to as the ‘hibernating gland’ owing to its presence in hibernating mammals [1,2], this tissue has been described in the literature under several different names and has undergone intermittent periods of intense scientific interest since the 1960s [3–13]. Consistently, the research questions that fueled this interest focused on characterizing its anatomical distribution and histology, its function as an endocrine or thermogenic organ, its role in aging, its involvement in energy balance and whether a homologous structure exists in humans [1]. Interest in BAT in humans only came sparingly and followed the same characterization trajectory as the earlier studies in rodents, beginning first with descriptions of its anatomical distribution, histology and presence with age [14,15]. As BAT is present in newborns but appeared to atrophy during infancy and into adulthood [14,16], it was commonly considered a vestigial organ, quiescent or irrelevant to human thermogenesis or energy metabolism. However, its remarkable role in preventing diet-induced obesity in rodents [10], maintained hope that if human BAT could be regenerated or reactivated this could have significant therapeutic potential for human obesity and its associated comorbidities. The mounting prospective studies demonstrating the presence of metabolically active BAT in adult humans [11,12,17,18] provided the necessary impetus to begin functionally characterizing BAT in humans. Thus, began a new wave of human BAT research examining both the structural and biochemical characteristics of human BAT but also the functional capacity of the organ. This review focuses on describing the functional characteristics of human BAT, the methodological approaches applied to examine these features in vivo and the critical gaps, controversies and future perspectives that may assist in continuing to move the field forward.

Anatomy and biomolecular characterization of human BAT: predicting function from form

The anatomical localization, distribution, histology and biomolecular characterization of BAT have been ongoing since the early interests in this tissue in hibernating mammals. From the earliest descriptions, it was evident that brown adipocytes had unique fundamental features. BAT was first histologically described in small mammals as multilocular, lipid-containing and light brown in color [1]. Its high vascularization, anatomical distribution near large and significant vascular routes combined with its high sensitivity to cold, led to the assertion that its primary function was to produce heat [19]. Indeed, the classical interscapular BAT depot in rats and its bilateral venous drainage could supply warm venous blood directly to the heart and other vital thoracic organs as well as the spinal cord and brain [19]. In humans, the interscapular BAT depot is most prevalent in infants (<2 years old) and appears to rapidly atrophy shortly thereafter, suggesting a similarly critical thermoregulatory role during a vulnerable period. In adult humans, BAT is most abundant in the supraclavicular region (Figure 1A) [21,22], where it envelopes the carotid artery. Individuals with the largest amounts of BAT [21,22] and demonstrating the greatest propensity to develop BAT in response to daily cold exposure [20], as determined by positron emission tomography (PET), also appear to demonstrate a high abundance of BAT in the paraspinal and perirenal region (Figure 1A). Combined, this evidence suggests BAT may serve a critical function in providing a continuous supply of warm blood to the brain, spinal cord and other vital organs.

BAT anatomical distribution and histological features.

Figure 1.
BAT anatomical distribution and histological features.

Whole-body [18F]FDG PET/CT image visualizing the accumulation of [18F]FDG in a male participant exposed to the cold for 3 h at the end of a 4-week cold acclimation protocol (A) (image modified from [20]). This image illustrates the largest, most common BAT depots (red arrows) in adult humans, which includes: supraclavicular, axillary, paraspinal, perirenal and mediastinal depots. BAT is identified according to unique histological features (B) which includes: (1) several small lipid droplets; (2) high vascularization, in part to provide circulating substrates to support thermogenesis, but more likely to dissipate heat generated by BAT; (3) rich sympathetic innervation, which allows for rapid ‘on-off’ response through the release of norepinephrine and subsequent binding to β-adrenergic receptors (β1-AR, β2-AR and β3-AR isoforms are expressed in human BAT) to stimulate intracellular lipolysis; (4) high mitochondrial content with highly developed cristae and expressing its unique uncoupling protein (uncoupling protein 1, UCP1), which uncouples oxidative phosphorylation.

Figure 1.
BAT anatomical distribution and histological features.

Whole-body [18F]FDG PET/CT image visualizing the accumulation of [18F]FDG in a male participant exposed to the cold for 3 h at the end of a 4-week cold acclimation protocol (A) (image modified from [20]). This image illustrates the largest, most common BAT depots (red arrows) in adult humans, which includes: supraclavicular, axillary, paraspinal, perirenal and mediastinal depots. BAT is identified according to unique histological features (B) which includes: (1) several small lipid droplets; (2) high vascularization, in part to provide circulating substrates to support thermogenesis, but more likely to dissipate heat generated by BAT; (3) rich sympathetic innervation, which allows for rapid ‘on-off’ response through the release of norepinephrine and subsequent binding to β-adrenergic receptors (β1-AR, β2-AR and β3-AR isoforms are expressed in human BAT) to stimulate intracellular lipolysis; (4) high mitochondrial content with highly developed cristae and expressing its unique uncoupling protein (uncoupling protein 1, UCP1), which uncouples oxidative phosphorylation.

In the early proposition that BAT might serve as a thermoregulatory organ, it was suggested that to fulfill this functional role it must be capable of rapid ‘on-off’ control [19], with evidence suggesting that sympathetic nerve supply could mediate such control. It was later confirmed that, in rodent interscapular BAT depot, sympathetic nerve fibers innervate both the vasculature of the tissue and the brown adipocytes themselves [23–25]. The central nervous system origin of the sympathetic nervous system (SNS) outflow to BAT was only fully characterized several decades later using neuroanatomical tract-tracing techniques [26–28]. The release of norepinephrine (NE) by the sympathetic nerve terminals that innervate BAT, acts on the β-adrenergic receptors (β-AR) present at the vasculature and cell surface of brown adipocytes [29] (Figure 1B). In humans, the proportion of each β-AR subtype present in BAT depots or the cell surface of brown adipocytes remains contentious, and may vary according to adipose depot [30,31]. The binding of NE to β-AR, in turn, activates the adenylyl cyclase/cAMP/protein kinase A (PKA) signaling cascade required for the hydrolysis of intracellular triglycerides (TG). The mobilized long-chain fatty acids (LCFA) released through this hydrolysis then activate a mitochondrial inner membrane protein uniquely expressed in brown adipocytes called uncoupling protein 1 (UCP1), initiating the UCP1-mediated thermogenesis described below and providing the necessary fuel to support this process. Transsynaptic viral tract-tracing studies also revealed that neurons that provide SNS outflow to stimulate BAT also receive input from a sensory system circuit originating at the interscapular BAT depot, suggesting a possible SNS-sensory feedback loop that controls lipolysis and therefore BAT thermogenesis [32]. Other membrane-bound ‘metabolite sensing’ G protein-coupled receptors that inhibit adenylyl cyclase activity (Gi-type), such as GPR109A and GPR109B bind to ketones or β-oxidation intermediate ligands and may also induce antilipolytic effects by providing some regulatory control on fatty acid flux in BAT [33]. Indeed, both in rodents and humans, the administration of nicotinic acid, a selective GPR109A agonist, suppresses BAT oxidative metabolism [34,35].

The heat-producing properties of BAT are conferred through the exceptionally high mitochondrial content, highly developed cristae and high level of UCP1 protein content [36–41]. Once activated, UCP1 increases proton transport across the inner mitochondrial membrane, dissipating the electrochemical proton gradient across the inner membrane that would otherwise drive ATP synthesis, thereby uncoupling mitochondrial respiration from ATP synthesis and producing heat as a by-product [42]. UCP1-dependent proton conductance is highly regulated and inducible, activated by LCFA [43] and inhibited by purine nucleotides [44,45]. Four models have been proposed to explain the interaction between these effectors, particularly the precise molecular regulation of LCFA-dependent UCP1 activation (comprehensively reviewed in [46,47]). In the first model, the ‘functional competition model’, it is suggested that fatty acids directly compete to remove the nucleotide inhibition of UCP1 by allosterically inducing a protonophoric conformation of UCP1 [48]. A second model, the ‘cofactor model’, posits that the LCFA associate with UCP1 to provide the protonatable carboxylate groups to form a proton transfer pathway [49]. A third model, known as the ‘cycling model’, ‘flip-flop model’ or ‘protonophoretic model’ proposes that protonated fatty acids cross the inner membrane (independently of UCP1), deprotonate in the mitochondrial matrix, then the disassociated fatty acid is subsequently transported back across the inner membrane by UCP1 [50,51], with UCP1 having only an indirect role in proton conductance. Finally, the prevailing model known as the ‘shuttling model’, proposes the simultaneous transport of one LCFA anion and one proton (albeit not necessarily through direct binding), but the inability of UCP1 to release the embedded fatty acid on either side of the membrane results in a net transfer of protons [41]. In this model, the LCFA is a necessary substrate, as alone it can be transported across the inner membrane independent of proton transport, but proton transport requires this LCFA, resulting in the LCFA, therefore, behaving as a kind of proton shuttle. Recent evidence using nuclear magnetic resonance (NMR) to examine human UCP1, identified specific LCFA binding sites on UCP1 closer to the matrix side of the protein which the authors argue, at least in humans, is compatible with UCP1 ‘flipping’ fatty acids across the membrane through the protein cavity (i.e. compatible with the ‘flip-flop/protonophoretic model’) [52].

According to the characteristic features of multilocular, UCP1-expressing adipocytes, in rodents, discrete BAT depots can be found in the interscapular, subscapular, axillary, cervical, perirenal and mediastinal regions [53], with the inguinal adipose depot also harboring a large proportion of brown adipocytes. While distinct ‘brown-like’ adipocytes that exhibit thermogenic properties are also found in certain white adipose tissue (WAT) depots, commonly referred to as ‘brite’ or ‘beige’ adipocytes, this heat production is conferred through UCP1-dependent and -independent mechanisms [54–58]. In humans, multilocular adipocytes containing a high level of UCP1 protein, high capillary density and rich sympathetic innervation or brown/beige adipocytes defined by their gene expression profile have been confirmed in supraclavicular [11,59–61], deep neck [62], retroperitoneal [63–66], epicardial [67–69] and omental [70] adipose tissues (Figure 1A). The presence of multilocular, thermogenic adipocytes exhibiting UCP1-independent thermogenic mechanisms remains to be demonstrated in humans. Investigators have argued that some of these defined areas have a greater capacity to increase their ‘brownability’ thereby increasing their capacity to produce heat and clear circulating substrates. It is important to note, however, that daily cold exposure, ranging from 10 days to 1 month of daily exposure, only increases the volume of BAT taking up glucose by 40–45% [12,20,71]. This may suggest then that human BAT plays a more localized role according to its anatomical localization, with the paraspinal depot ensuring nerve conductivity, supraclavicular depot ensuring a continuous supply of warm blood to the brain, and epicardial depot serving as a NEFA sink to protect against fatty acid overexposure to the myocardium. Consistently, observations from studies examining human BAT distribution demonstrate that there is tremendous heterogeneity in the amount of UCP1-expressing multilocular adipocytes contained within an adipose tissue depot, even within the largest and most prevalent supraclavicular BAT depot [72]. In addition, there is tremendous interindividual variation in the number of adipose depots presenting metabolic activity suggestive of harboring brown adipocytes or the degree to which an individual can increase the presence of brown adipocytes within a given depot [20,22,73–75]. Although several studies have characterized the histological and biomolecular features of human BAT, few have functionally characterized human BAT in vivo beyond the largest depot in the supraclavicular area. The following section will describe possible approaches to functionally characterize human BAT in vivo, our current understanding of the largest and most commonly studied human BAT depot and its contribution to thermoregulation and whole-body energy metabolism.

In vivo assessment of human BAT

For studies of BAT in humans, non-invasive methods are preferred because they do not carry surgical risks and discomforts [76,77], and do not disrupt normal tissue function. This section provides an overview of non-invasive methods used to study BAT. A brief description of the different modalities is provided, followed by BAT-specific applications (summarized in Table 1).

Table 1.
Summary of most common non-invasive methods for BAT studies
MethodApplicationStrengthsWeaknesses
PET Overall PET methods Quantitative
Highly sensitive
Variety of molecular probes 
Radiation exposure
High cost
Limited availability 
Glucose metabolism (18F-FDG) Available in most PET centers
Well-characterized
Gold standard for BAT delineation 
Modulated by insulin levels and sensitivity
Not a primary substrate for BAT thermogenesis 
Fatty acid metabolism (18F-FTHA) Alternative energy substrate of BAT
Can be administered orally to track dietary fatty acid metabolism 
Not a primary substrate for BAT thermogenesis
Free fatty acids may not be the preferred source of fatty acids 
Perfusion (15O-H2O, 15O-CO) Gold standard for perfusion/blood volume Technically challenging
High cost 
Mitochondrial content (11C-PBR28) Highlights an important BAT feature Not widely available
Needs further validation in BAT 
Sympathetic innervation (11C-HED, 11C-MRB) Highlights an important BAT feature Not widely available
Needs further validation in BAT 
Oxygen consumption (15O-O2Gold standard for oxidation Technically challenging
High cost 
SPECT Overall SPECT methods Quantitative
Variety of molecular probes
Lower cost than PET 
Radiation exposure
Poor time resolution 
Mitochondrial content (99mTc-MIBI, 99mTc-tetrofosmin) Highlights an important BAT feature Needs further validation in BAT 
Sympathetic innervation (11I-MIBIG) Highlights an important BAT feature Needs further validation in BAT 
MRI Overall MRI methods No radiation
Good anatomical details 
High cost
Low sensitivity 
Fat content (chemical shift-encoded methods, e.g. Dixon) High spatial resolution
Short scan times
Clinical sequences available 
Complex modeling
Does not inform about triglyceride composition 
Triglyceride droplet size (diffusion-weighted MRI) Highlights an important BAT feature Sensitive to motion
Needs further validation in BAT 
Mitochondria density (T2* mapping) Endogenous contrast Many confounding factors
Complex sequence implementation 
Oxygen consumption (BOLD) Endogenous contrast Many confounding factors 
MRS Overall MRS methods No radiation
Information about chemical structure 
Low spatial resolution
Low sensitivity
High cost 
Fat content (proton spectroscopy) Information about triglyceride composition
Simple modeling 
Sensitive to motion
Sensitive to magnetic field inhomogeneity
Possible contamination by neighboring tissues 
Thermogenesis (MR thermometry) Endogenous probe
Deep tissue penetration 
Low sensitivity 
Contrast ultrasound Perfusion No radiation
Low cost
Portable 
Needs further validation in BAT 
Thermal imaging Thermogenesis No radiation
Low cost
Portable 
Limited to tissues close to the skin
Low spatial resolution
Numerous confounding factors 
NIRS Oxygen consumption No radiation
Low cost
Portable 
Limited to tissues close to the skin
Low spatial resolution
Numerous confounding factors 
MethodApplicationStrengthsWeaknesses
PET Overall PET methods Quantitative
Highly sensitive
Variety of molecular probes 
Radiation exposure
High cost
Limited availability 
Glucose metabolism (18F-FDG) Available in most PET centers
Well-characterized
Gold standard for BAT delineation 
Modulated by insulin levels and sensitivity
Not a primary substrate for BAT thermogenesis 
Fatty acid metabolism (18F-FTHA) Alternative energy substrate of BAT
Can be administered orally to track dietary fatty acid metabolism 
Not a primary substrate for BAT thermogenesis
Free fatty acids may not be the preferred source of fatty acids 
Perfusion (15O-H2O, 15O-CO) Gold standard for perfusion/blood volume Technically challenging
High cost 
Mitochondrial content (11C-PBR28) Highlights an important BAT feature Not widely available
Needs further validation in BAT 
Sympathetic innervation (11C-HED, 11C-MRB) Highlights an important BAT feature Not widely available
Needs further validation in BAT 
Oxygen consumption (15O-O2Gold standard for oxidation Technically challenging
High cost 
SPECT Overall SPECT methods Quantitative
Variety of molecular probes
Lower cost than PET 
Radiation exposure
Poor time resolution 
Mitochondrial content (99mTc-MIBI, 99mTc-tetrofosmin) Highlights an important BAT feature Needs further validation in BAT 
Sympathetic innervation (11I-MIBIG) Highlights an important BAT feature Needs further validation in BAT 
MRI Overall MRI methods No radiation
Good anatomical details 
High cost
Low sensitivity 
Fat content (chemical shift-encoded methods, e.g. Dixon) High spatial resolution
Short scan times
Clinical sequences available 
Complex modeling
Does not inform about triglyceride composition 
Triglyceride droplet size (diffusion-weighted MRI) Highlights an important BAT feature Sensitive to motion
Needs further validation in BAT 
Mitochondria density (T2* mapping) Endogenous contrast Many confounding factors
Complex sequence implementation 
Oxygen consumption (BOLD) Endogenous contrast Many confounding factors 
MRS Overall MRS methods No radiation
Information about chemical structure 
Low spatial resolution
Low sensitivity
High cost 
Fat content (proton spectroscopy) Information about triglyceride composition
Simple modeling 
Sensitive to motion
Sensitive to magnetic field inhomogeneity
Possible contamination by neighboring tissues 
Thermogenesis (MR thermometry) Endogenous probe
Deep tissue penetration 
Low sensitivity 
Contrast ultrasound Perfusion No radiation
Low cost
Portable 
Needs further validation in BAT 
Thermal imaging Thermogenesis No radiation
Low cost
Portable 
Limited to tissues close to the skin
Low spatial resolution
Numerous confounding factors 
NIRS Oxygen consumption No radiation
Low cost
Portable 
Limited to tissues close to the skin
Low spatial resolution
Numerous confounding factors 

Modalities to study BAT in vivo

PET and SPECT

PET and single-photon emission computed tomography (SPECT) are both nuclear medicine techniques that generate three-dimensional concentration maps of a radiotracer [78]. The radiotracer is a molecule in which a stable atom has been replaced by a radioisotope (e.g. 12C replaced by 11C). It is administered to the participant in picomolar concentration (10−12 M) to avoid any pharmacological effect. Its distribution in tissues is detected by measuring photons from radioactive decay. Because PET and SPECT are functional imaging methods, they can be coupled with computed tomography (CT) for anatomical reference and image correction (e.g. attenuation of signal by tissues). The main differences between PET and SPECT scanners are the type of radioisotope and the mode of detection.

PET uses positron emitters and detects the two 511 keV photons emitted at a ∼180° angle during electron–positron annihilation. The small variation (∼0.25°) in emission angle, known as acollinearity, is due to the residual kinetic energy of the electron–positron pair at annihilation and contributes to the fundamental limits of spatial resolution in PET [79]. The detector is a static ring surrounding the subject (see [80]). Because photons are emitted at a known angle and detected in coincidence, it can pinpoint where the annihilation occurred and produce three-dimensional images. Also, because detection occurs at all angles simultaneously, it is possible to retrospectively specify the time sampling (e.g. one 10 min image frame versus ten images at 1 min intervals), providing tremendous flexibility in quantifying dynamic organ fluxes using dynamic acquisitions. However, most positron-emitting radiotracers are produced via cyclotron and have short half-lives (minutes to hours) limiting their use to specialized imaging centers. Also, all photons from positron annihilation have the same energy. Therefore, it is impossible to distinguish signals from different radioisotopes or from the parent compound and its metabolites.

SPECT detects single gamma photons emitted directly by the decaying atom. These photons have characteristic energies specific of their parent atom. Therefore, it is theoretically possible to distinguish two radiotracers based on their energies, although this is not routinely done. However, parent compounds and metabolites are still indistinguishable. The photons are detected using one or more cameras rotating around the subject to acquire different planes. Because photon emission is isotropic, collimators are used to filter photons according to their angle of incidence in order to derive the spatial dose distribution. The limited number of cameras and the time needed to acquire each image plane limits the use of SPECT for dynamic imaging [81]. SPECT images also tend to be noisier compared with PET due to the filtering of photons by collimators [82]. However, SPECT is a more widespread technique because of lower scanner costs and easy access to generator-produced radioisotopes [83].

The possibilities offered by PET and SPECT for metabolic imaging are mostly limited by the radiotracers approved for humans. Radiation exposure is also a concern for longitudinal or pediatric studies. However, there are several advantages to using PET for metabolic imaging. First, two acquisition modalities are possible using PET including whole-body ‘static scans’, which provide the biodistribution or relative uptake of radiotracers (reported as ‘standard uptake value (SUV)’), and more spatially limited ‘dynamic scans’ which directly measures fluxes of tracers in and out of tissues (see [80]). Static PET scans (Figure 2, left side) are typically applied using radiotracers with longer half-lives (e.g. [18F]2-fluoro-2-deoxy-d-glucose, [18F]FDG, or 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid, [18F]FTHA) which allows for the semi-quantitative determination of cumulative tracer uptake among different organs over a long period of time, which has been particularly useful in tracking the metabolic fate of dietary fatty acid [73,87]. While being very useful in determining the relative integrated uptake of a substrate among tissues, it does not provide quantitative fluxes of this substrate in or out of the tissue. In contrast, dynamic PET imaging non-invasively quantifies metabolic fluxes or receptor binding using a broad range of radiotracers but requires long acquisition times, the determination of blood and tissue tracer and metabolite concentrations [88] and the application of linearization [85] or compartmental modeling [86,89] (Figure 2, right panel) or spectral analysis [90]. The deconvolution of the time-activity-curves provides greater detail on the possible metabolic fate of substrates, in contrast with static PET images. The most significant advantage of dynamic PET imaging especially, lies in its remarkable sensitivity, reaching the picomolar range (10−12 M) compared with MRS which can detect changes in the millimolar range (10−3 M) [91].

PET image analysis pipeline.
Figure 2.
PET image analysis pipeline.

Illustrations on far left demonstrate the theoretical fate of the radiotracer. The PET static image shows the radiotracer accumulation over a 30–40 min period. By acquiring several static images at different time intervals, time-activity-curves can be constructed, referred to as dynamic data. Here, the radiotracer uptake and washout in BAT is very different between intravenous (i.v.) [11C]acetate, [18F]FDG and [18F]FTHA which provides additional information compared with static imaging (data derived from [13,35]). For oral (p.o.) [18F]FTHA, only the equilibrium phase of radiotracer distribution is available because the uptake phase occurs prior to the scan (data derived from [73]). However, blood samples were taken throughout the experiment to assess [18F]FTHA concentration. It is possible to apply models such as monoexponential decay [84] or Patlak Blasberg [85] on the dynamic data to derive quantitative information about uptake. For Patlak, radiotracer concentration must be measured in the blood from the moment of administration, but tissue concentration can be measured only at equilibrium. For the monoexponential decay model, only the peak and decay phase of tissue concentration needs to be measured. Compartmental modeling (not shown here) is also possible [86]. Cp: plasma radiotracer concentration, CT: tissue tracer concentration.

Figure 2.
PET image analysis pipeline.

Illustrations on far left demonstrate the theoretical fate of the radiotracer. The PET static image shows the radiotracer accumulation over a 30–40 min period. By acquiring several static images at different time intervals, time-activity-curves can be constructed, referred to as dynamic data. Here, the radiotracer uptake and washout in BAT is very different between intravenous (i.v.) [11C]acetate, [18F]FDG and [18F]FTHA which provides additional information compared with static imaging (data derived from [13,35]). For oral (p.o.) [18F]FTHA, only the equilibrium phase of radiotracer distribution is available because the uptake phase occurs prior to the scan (data derived from [73]). However, blood samples were taken throughout the experiment to assess [18F]FTHA concentration. It is possible to apply models such as monoexponential decay [84] or Patlak Blasberg [85] on the dynamic data to derive quantitative information about uptake. For Patlak, radiotracer concentration must be measured in the blood from the moment of administration, but tissue concentration can be measured only at equilibrium. For the monoexponential decay model, only the peak and decay phase of tissue concentration needs to be measured. Compartmental modeling (not shown here) is also possible [86]. Cp: plasma radiotracer concentration, CT: tissue tracer concentration.

Magnetic resonance imaging/spectroscopy

NMR is a physical phenomenon in which spins of nuclei align with a static magnetic field and produce magnetization. This magnetization can be measured using radiofrequency pulses and an antenna [92]. Since the environment of the spins affects the NMR signal (notably its frequency content), this method is used in chemistry to derive the chemical composition of samples. The intensity of the NMR signal depends on the number of spins and the strength of the magnetic field. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are medical applications of NMR. Clinical scanners have relatively low magnetic fields (1.5 and 3 T) and, thus, low sensitivity. They are limited to studies of chemical species present in millimolar or greater concentrations, such as protons from water and fat, phosphorus from ATP and phosphocreatine, and exogenous agents (e.g. 13C or 2H-labeled compounds). Moreover, each type of nucleus requires dedicated hardware for detection, which increases costs and the complexity of experiments.

The difference between MRI and MRS lies in the spatial encoding of the signal [93,94]. MRI uses modulations of the magnetic field called ‘gradients’ to encode spatial information in the detected signal. The result is an image with each voxel representing the global contribution of all detectable molecules in that region. Whereas, MRS pools the signal from a large region to produce a detailed spectrum showing the contribution of each chemical species (see [95,96] for comprehensive review). Consequently, MRI does not provide direct information about the chemical composition of tissues, but it has more detailed spatial information than MRS, whereas MRS provides information about metabolites. It is, however, possible to create specific MRI sequences to derive properties of the signal such as relaxation times (T1, T2, T2*) or frequency content (chemical shift) which can be related to tissue composition.

Ultrasound and optical imaging

Ultrasound is based on the ratio of absorption and reflection of sound waves by tissues. It is used to study structure, but also blood flow through means such as doppler [97] and imaging of exogenous microbubbles (contrast-enhanced ultrasound) [98]. Many optical-based methods are available for in vivo studies. Some of them relying on the injection of fluorescent dyes are limited to animal studies and will not be discussed here. The leading optical methods used to study human BAT are thermal imaging and near-infrared spatially resolved spectroscopy (NIRS). Thermal imaging is simply the measure of infrared radiation emitted by a body using a thermographic camera and allows for the calculation of surface temperatures [99]. NIRS, however, involves sending radiation in the near-infrared spectrum and detecting the absorption at specific wavelengths characteristic of compounds such as deoxyhemoglobin and oxyhemoglobin [100]. Both methods are widely available, inexpensive and portable. However, infrared and near-infrared wavelengths are directly absorbed by tissues which limits the use of these methods to tissues close to the skin.

Application of non-invasive methods to study BAT morphology

BAT is distinguishable from WAT by its reduced fat content, smaller triglyceride droplets, high mitochondrial density, high vascularization and sympathetic innervation. These characteristics are present whether BAT is active or inactive.

Triglyceride content and droplet size

The fat content of BAT has been investigated by CT [17,101] and by chemical shift-encoded MRI/MRS (notably the MRI Dixon method) [102,103] (Figure 3). There is a good correlation between conventional single-energy CT and MRI [104]. Both modalities show a tendency towards lower fat fractions in BAT compared with WAT [105,106]. However, BAT and WAT fat contents are affected by factors such as age [107], body weight [108] and metabolic health [109,110], and there is no absolute threshold do distinguish BAT from WAT in humans [111]. Dual-energy CT has been suggested as an alternative to conventional CT to discriminate BAT and WAT based on their different absorption profiles at two X-ray energies [112]. This method remains to be validated in diverse subject populations. For both conventional and dual-energy CT, the radiation doses may be too high for certain patient populations or longitudinal studies. Therefore, fat quantification is increasingly performed by MRI/MRS. However, these modalities are more technically challenging than CT. Special considerations for MRI/MRS include accounting for different relaxation times of water and fat components, which can change depending on their respective proportions [113]. A sequence with low flip angle to minimize T1 relaxation effects, as well as multiple echoes (generally 6), improve fat quantification [114]. The model used in the fat–water separation algorithm also influences the calculated fat fraction [115]. For this reason, quantification methods with fewer model constraints have been suggested [116].

In vivo assessment of human BAT.
Figure 3.
In vivo assessment of human BAT.

Global view of some non-invasive in vivo functional characterization tools to study human BAT. Words in black represent PET/CT methods, in red SPECT methods, in gray MRI/MRS methods and brown refers to infrared imaging. * represents tracers not used in humans yet, but possibly in the pre-clinical to clinical pipeline.

Figure 3.
In vivo assessment of human BAT.

Global view of some non-invasive in vivo functional characterization tools to study human BAT. Words in black represent PET/CT methods, in red SPECT methods, in gray MRI/MRS methods and brown refers to infrared imaging. * represents tracers not used in humans yet, but possibly in the pre-clinical to clinical pipeline.

Triglyceride droplet size

The size of triglyceride droplets is harder to quantify by imaging than the total fat content because image voxels are too large to resolve single cells. A method suggested to infer droplet size is diffusion-weighted MRI in which the speed and direction of diffusing water molecules can be estimated [117]. In a group of cells with multiple small lipid droplets, water will diffuse further and in a more isotropic manner than in a group of cells with single large droplets. A major limitation of diffusion-weighted imaging for BAT studies is its sensitivity to subject motion combined with the long scan times.

Mitochondrial density

Mitochondrial content can be assessed by some SPECT radiotracers such as 99mTc-MIBI [118–120] and 99mTc-tetrofosmin [121] that are sensitive to membrane potential or by PET using the translocator protein radio-ligand [11C]PBR28 [122] (Figure 3). Due to the high iron content of mitochondria, T2*-weighted MRI or T2* mapping have also been suggested to distinguish BAT from WAT [123,124]. However, there is no validated T2* threshold for human BAT [125] and many other factors, such as susceptibility artifacts from the lungs and change in hemodynamic parameters, can modify local T2* values [126]. Moreover, due to the complexity of the water–fat mixture, multi-echo sequences with up to 12 echoes are required to properly quantify BAT T2* [114]. These sequences are lengthy and cannot be performed in a single breath hold to limit motion artifacts.

Vascular density, perfusion and blood volume

Although SNS stimulation of BAT typically results in an increase in tissue perfusion and therefore an increase in circulating energy substrates and dissipation of heat through the bloodstream, BAT perfusion has been the focus of relatively few studies. Most studies examining tissue perfusion have been performed using [15O]-labeled PET radiotracers to measure water perfusion ([15O]H2O) [127–130] and blood volume ([15O]CO) [128,129] (Figure 3). These radiotracers provide a more realistic measure of tissue perfusion than larger molecules such as gadolinium chelates in MRI [131], but they suffer from the short half-life of 15O (2-min), its high production cost and poor intrinsic image resolution (long positron range). Contrast ultrasound has also been suggested to characterize BAT blood flow [132], but quantitative methods have yet to be implemented for this tissue.

Sympathetic innervation

Radiotracers, such as NE analogs (123I-MIBIG in SPECT [133–135]; 11C-HED in PET [136]) and NE transporter ligands (11C-MRB in PET [137]), are available to highlight the sympathetic innervation of tissues (Figure 3). These radiotracers remain limited to specialized centers and have not been routinely used for BAT assessment [136]. The main drawbacks of morphological targets for BAT assessment are the lack of information about BAT thermogenic activity and the absence of universal thresholds to distinguish between BAT and WAT. Additional assessments under thermal or pharmacological challenges are needed to measure BAT volume and metabolic activity using these approaches.

Application of non-invasive methods to study BAT function

BAT function has been studied in two different ways, either indirectly through its uptake of energy substrates or directly through assessment of heat production or substrate oxidation.

Energy substrate uptake

The revived interest in human BAT originates primarily as a result of challenges this tissue posed in nuclear medicine, with the accumulation of [18F]FDG within the tissue often eliciting false positives in the detection of neoplastic pathologies, such as tumors. What was seen as a nuisance in nuclear medicine, became a source of great interest for BAT physiologists [138]. [18F]FDG is transported in a cell through the same transporters as endogenous glucose. Once transported [18F]FDG is phosphorylated by hexokinase to form [18F]FDG-6-phosphate and does not participate any further in glycolysis, subsequently being irreversibly trapped within the cell and accumulating in proportion to the glycolytic rate [139]. Non-phosphorylated [18F]FDG can return to the circulation and be taken up elsewhere (Figure 2). Because [18F]FDG PET/CT had demonstrated to be reliable in identifying BAT in adult humans, it became the first method proposed to characterize BAT volume and metabolic activity in vivo [11,12,18]. Initially, many studies relied on incidental findings in clinical populations [138,140–142]. It was later shown that BAT uptake of glucose was highly dependent on factors such as ambient temperature [21,143,144], cold acclimation [20,71,74] stressing the need for controlled activation protocols. [18F]FDG PET remains the most common functional assessment tool to study human BAT [145] due to its wide availability in clinical PET centers and well-characterized pharmacokinetic profile [146]. However, several studies have demonstrated an uncoupling between BAT thermogenesis and glucose uptake [13,35,147,148] and that insulin production and insulin sensitivity play a large role in BAT glucose uptake [13,149,150]. Therefore, BAT studies in insulin-resistant populations may be biased if they rely only on [18F]FDG as a surrogate of BAT thermogenesis. Moreover, studies have shown that the primary energy substrate for BAT thermogenesis is intracellular TG [35]. In this context, it is probable that glucose and other substrates in the bloodstream will not fuel BAT thermogenesis until triglyceride stores are depleted to some level [151].

Intracellular triglyceride depletion can be assessed by the fat content methods mentioned previously (CT and chemical shift-encoded MRI/MRS) with repeated measures before, during and after BAT stimulation [101,151] (Figure 3). To this day, studies have reported various ranges of triglyceride depletion following BAT stimulation [152–154]. These differences may be attributed to factors such as BAT stimulation protocols and BAT segmentation methods [155]. As mentioned previously, changes in tissue blood volume may also impact fat fractions, although this has never been confirmed [104]. Finally, it is important to note that these methods only measure the depletion of lipids, not the fate of these lipids (e.g. oxidation versus release in the bloodstream). Indeed, in vitro data suggest that only ∼50% of fatty acids released from the hydrolysis of intracellular TG in brown adipocytes is oxidized [156].

Circulating lipids are another less studied energy substrate for BAT. The LCFA PET analog, [18F]FTHA, can be used for this purpose, administered by intravenous injection [13,17,157,158], but also orally to trace the postprandial metabolism of lipids [73] (Figures 2 and 3). [18F]FTHA is an 18F-labelled LCFA analog with a thioether on the sixth carbon. Like other NEFA, it is bound to albumin in the plasma and must ultimately disassociate from albumin to enter a cell. Once taken up by tissues it can be activated by acyl-CoA synthetase and transported within the mitochondria where it can undergo the initial steps of β-oxidation (Figure 2). Following the formation of the first two acetyl CoA, the remaining part of the fatty acid chain is trapped within the mitochondria as further oxidation is blocked at its sulfur heteroatom located at the sixth carbon of the fatty acid chain [159]. [18F]FTHA may also be incorporated into complex lipids, such as phospholipids and TG [160]. However, in contrast with another LCFA PET analog, [11C]palmitate (discussed below), it is not possible to distinguish between the oxidative and nonoxidative disposal of this tracer. In addition, circulating fatty acids may not be the preferred lipid source for BAT. Indeed, animal models suggest that chylomicrons and VLDL, collectively known as triglyceride-rich lipoproteins (TRL), are a significant fuel source for stimulated BAT [161–163]. The oral administration of [18F]FTHA, given with a standard liquid meal, has provided a unique opportunity to track the delivery of a dietary fatty acid into the circulation, where it presents largely within the TG of a chylomicron (a large TRL), and ultimately carried to various organs including BAT [73,87]. Where this method has its limitations, is in the variable latency with which these tracers transform and remain in relatively inaccessible compartments (i.e. gastrointestinal tract, splanchnic circulation, lymphatic system), as chylomicrons only appear slowly in circulation over hours after a meal. The dynamic nature of TRL also inherently results in a continual change in size and composition. As a result of this continual change, inferences can only be made on how TRL are handled based on the proportion of the positron-emitting metabolites in circulation. The relatively low bioavailability of dietary fatty acids (relative to what is ingested) limits our understanding of how TRL are handled by BAT in humans. There is, therefore, a need for a well-validated TRL tracer.

Thermogenesis and oxidative metabolism

For researchers striving to harness BAT for weight loss and maintenance, the parameter of interest is the relative contribution of BAT thermogenesis to whole-body energy expenditure. Direct measures of heat production can be achieved using temperature sensors [164,165] or infrared imaging [166,167], although results from both methods do not always coincide [168]. These methods are inexpensive, do not carry significant risks and can be used outside of a laboratory setting [169,170]. Their application, however, is limited to superficial BAT depots such as supraclavicular BAT and should be used with the understanding that it carries several critical limitations. Insulation by subcutaneous fat [171–174], production of heat by adjacent muscles [130] as well as the delivery of warm blood through large vessels that are near the supraclavicular fossa [136] are critical confounding factors for this method that limit its reliability. Some groups have suggested protocols to control these factors [175,176], yet BAT assessment by infrared thermography remains to be validated in humans [177]. An alternative to optical thermography, is MR-based thermometry. By measuring the difference between the water frequency (temperature-dependent) and fat methylene frequency (temperature-independent), it is possible to assess temperature changes [178]. However, the shift in water resonance is small (−0.01 ppm/°C) making it difficult to reliably measure the temperature variations expected for BAT [114].

To circumvent the sensitivity issues of temperature measures, many groups prefer to apply the principles of indirect calorimetry to quantify thermogenesis by measuring oxidative metabolism. Oxygen consumption by BAT has been measured using [15O]O2 PET and constitutes the most direct in vivo method to assess oxidative metabolism [129,130]. However, it suffers from the same drawbacks as other [15O] methods, with its short half-life, high cost and poor image resolution. A more convenient, method is the assessment of [11C]CO2 production from [11C]acetate metabolism [20,35,73,179] (Figure 2). Although [11C] production requires an on-site cyclotron because of its 20 min half-life, it is much cheaper to produce than [15O]. The main limitation of [11C]acetate is the need for complex pharmacokinetic model to distinguish oxidation, lipid synthesis and blood flow contributions to the signal [86]. Finally, NIRS [180,181] and T2*-weighted (BOLD) MRI [182] maybe used to apply the Fick principle to determine oxygen consumption, by assessing blood flow and tissue extraction of oxygen via changes in the oxyhemoglobin/deoxyhemoglobin ratio. However, this ratio is influenced by a variety of factors besides oxygen consumption, such as, vasoconstriction [183]. Also, as mentioned previously, NIRS is limited to tissues close to the skin [184] and its spatial resolution is poor.

Future avenues

Many other non-invasive tools are currently being tested in humans or animal models. Below are a few select examples of methods susceptible to be applied in future human BAT studies.

PET

Different radiotracers have been suggested to follow BAT uptake of lipids. Among these, [11C]palmitate is very similar to [18F]FTHA as they are both LCFA. Due to the short half-life of [11C], [11C]palmitate can be more easily combined with other PET radiotracers for same-day experiments. Moreover, it is identical with its parent molecule [12C]palmitate, unlike [18F]FTHA which is modified to include a [18F] atom. On the downside, pharmacokinetic modeling of [11C]palmitate is complex and several blood metabolites must be accounted for [185]. [18F]BODIPY-triglyceride-containing chylomicron-like particles [186,187] and other similar radiotracers are also currently in development with the hope of visualizing the uptake of fatty acids from TRL. Unfortunately, the instability of the [18F]BODIPY-triglyceride-containing chylomicron-like particle in vivo and its uncertain metabolic fate may ultimately limit its suitability for use in humans.

Other molecular targets useful for understanding BAT activation and potential dysfunctions, such as adenosine A2A receptor antagonists (e.g. 11C-TMSX) [188] and CB1 receptor inverse agonist radioligands (e.g. 18F-FMPEP-d2) [189] have recently been applied.

MRI and MRS

Among MR-based methods, hyperpolarization seems most promising. Briefly, hyperpolarization consists in increasing the number of spins aligned in the same direction (polarized) that can contribute to the signal [190]. Among hyperpolarized probes, 129Xe is a candidate for MR thermometry. This probe is highly soluble in lipids and has a temperature-dependent shift in frequency 21 times greater than water (−0.21 ppm/°C). This large shift combined with the high signal generated by hyperpolarization makes it possible to measure small shifts in BAT temperature [191, 192]. Hyperpolarized 129Xe is already approved for use in humans, notably for studies of lung function. Measures of oxidative metabolism with hyperpolarized [13C]pyruvate are also an alternative to [11C]acetate PET. Because MRS of [13C]pyruvate can distinguish between the parent molecule and its metabolites, it would allow direct assessment of TCA cycle intermediates and end-products [193,194]. Hyperpolarized [13C]pyruvate is also approved for use in humans, notably for cancer studies. Conventional [13C] MRS without hyperpolarization is also possible with exogenous enrichment similar to the current stable isotope methods [195]. It is a more cost-effective option requiring only the 13C antenna and not the costly hyperpolarization devices.

Alternatives to chemical shift-encoded MRI have also been proposed to measure fat content. For example, Z-spectrum imaging, a method based on saturation of the signal at multiple frequencies. This method is especially robust to magnetic field homogeneities and does not require a priori information about the fat model [196]. However, it involves longer scan times (a few minutes) compared with chemical shift-encoded MRI (a few seconds).

Finally, standard chemical-shift-encoded MRI/MRS and Z-spectrum imaging assess the fat content of tissues at a macroscopic level. Methods based on quantum coherences have been proposed to probe the microscopic interactions between fat and water protons within single cells [197]. These methods are still in their infancy and issues of poor signal-to-noise ratio as well as implementation on clinical scanners will have to be resolved [198].

Others

Microwave radiometry, a technique which probes thermally generated microwave noise emissions, has been suggested as an alternative to infrared thermography [122]. Microwaves, unlike infrared wavelengths, have deep tissue penetration and could be used to probe changes in BAT temperature during activation. However, the application of this method to biological research is new and several technical limitations, such as poor spatial resolution, must be addressed.

Multispectral optoacoustic tomography has also been proposed as an alternative to NIRS [199]. It uses laser pulses in different wavelengths to generate ultrasound waves through the thermo-elastic expansion of the tissue. Depending on the wavelength used, this method can inform on the oxyhemoglobin/deoxyhemoglobin ratio or other tissue properties such as fat content.

Several modalities exist for in vivo functional studies of human BAT. However, each method targets a limited number of BAT characteristics. They must be carefully combined to obtain a global picture of BAT function and avoid biases. In this context, PET–MRI offers many opportunities to perform anatomical and functional measures of BAT simultaneously. Less costly alternatives such as a combination of SPECT radiotracers should be explored. Because many imaging techniques involve the delivery of exogenous agents by the bloodstream, perfusion must be considered as a confounding factor. Changes in BAT blood volume and blood flow during cold exposure have been documented in a few studies, but their effects on imaging probe delivery and kinetics remain mostly unknown. Reliable and cost-effective methods need to be explored for systematic perfusion measurements.

Functional characteristics of human BAT

Using these valuable non-invasive imaging tools, significant progress has been made in the in vivo functional characterization of human BAT since the first prospective [18F]FDG PET studies [11,12,138,142]. More specifically, studies have been largely focused on quantifying BAT mass, its anatomical distribution, plasticity, thermogenic capacity and utilization of circulating and intracellular sources of energy.

Tissue ‘mass’ and plasticity

Original histological evidence, based on the presence of multilocular adipocytes and mitochondrial enzyme activity, provided general ideas of the anatomical distribution of human BAT with age [14] and its prevalence among certain populations [15]. These necropsy studies provided evidence that BAT is widely distributed among several depots in the first decade of life but rapidly atrophies thereafter [14] and that cold acclimatization, from natural cold exposure, could potentially assist in retaining or reactivating oxidative metabolism, at least in the supraclavicular BAT depot [15]. Because these tissues were excised during necropsies it was impossible to assess the thermogenic properties of this BAT in vivo. Others provided indirect evidence that repeated cold exposure (12–14°C air, 8 h per day for 31 consecutive days) could increase the thermogenic capacity of a non-shivering thermogenic mechanism [200], which many attributed to an increase in BAT size or activity. It is only recently that tools have been available to directly address questions surrounding the distribution, plasticity and thermogenic capacity of human BAT.

One of the first challenges in identifying BAT in vivo in humans and quantifying its mass and distribution, was in establishing evidence-based identification criteria. In the early rush to investigate the metabolic role of human BAT, various PET/CT acquisition and reconstruction protocols and [18F]FDG PET/CT thresholds were applied, under varying stimulation conditions (see [201] for detailed overview of varied approaches). This ultimately led to several experts in the field of human BAT forming a panel focused on developing a unified approach to study human BAT using static whole-body [18F]FDG PET/CT imaging [202]. From these earlier studies and the suggestions provided by this panel, it was evident that the imaging thresholds to quantify BAT mass and distribution would require two distinguishing tissue characteristics: one to identify adipose tissue and another to identify high metabolic activity that is beyond the limits of classical WAT. In the former, fat fraction thresholds are generally applied either using CT Hounsfield units (typically −10 to −190 HU) [202] or proton density fat fraction by MRI (typically a proton density fat fraction between 30% and 100%) [103] which account for all adipose tissue. Using [18F]FDG PET, a SUVmean ≥ 1.5 has commonly been used as a minimal metabolic threshold to distinguish less metabolically active WAT from relatively more active BAT [201]. Stricter thresholds of −50 to −240 for CT Hounsfield units and SUVmean > 2.0 for [18F]FDG PET have also been applied [101,128,203], which result in significantly lower BAT volumes [201], but likely improve repeatability between testing sessions, imaging modalities and populations [204].

The addition of adipose tissue regions accumulating [18F]FDG at an SUVmean threshold ≥ 1.5 is calculated to determine ‘[18F]FDG-positive fat’ (referred to as ‘BAT volume’), reported in milliliter or converted to grams by multiplying by the density of adipose tissue (0.925 g ml−1; [205]). This particular criteria has proven to be problematic in estimating ‘BAT volume’ in individuals with high BAT fat fractions or insulin resistance, who accumulate significantly less [18F]FDG in BAT yet still present significant BAT oxidative metabolism and normal fatty acid uptake [13]. Regardless, using this static whole-body [18F]FDG PET/CT criteria, ‘BAT volume’ is generally reported to be between 50 and 150 ml (or 45–135 g), which represents 0.06–0.08% of total body mass of an average man or woman. This represents a significantly lower proportion of body weight than a warm-acclimated C57BL/6 mouse (∼0.2% of body mass; Figure 4). To date, the most effective means of increasing ‘BAT volume’ in humans is through daily cold exposure. Whether being exposed to 15–16° cold air for 6 h per day for 10 consecutive days [74], sleeping in a cold room at 19°C for a month [71], or being exposed 2 -h daily for 5 days per week for 4 weeks [20], ‘BAT volume’ increases by 40–45%. This increase in ‘BAT volume’ is also of the same magnitude as what is observed in cold-acclimated mice [210]. This suggests that there may be an upper limit to increasing ‘BAT volume’ in humans (as in mice), although colder, more prolonged, and more frequent exposures may be necessary to confirm this. Daily pharmacological stimulation of BAT using the β3-AR agonist mirabegron, has been shown to have no effect on ‘BAT volume’ in individuals given 50 mg/day for 12 weeks [216], but reportedly doubled in women given 100 mg/day for 4 weeks [217]. The latter is likely a significant overestimation associated with the measure of ‘BAT volume’ using [18F]FDG PET/CT criteria. The absence of a reliable measure of BAT volume in humans remains a significant gap in accurately estimating the thermogenic contribution of BAT and its plasticity in response to environmental or pharmacological stimulation.

Mouse and human cold-induced whole-body and BAT thermogenesis.

Figure 4.
Mouse and human cold-induced whole-body and BAT thermogenesis.

Mouse data represents data obtained from C57BL/6 mice, as it represents the most common laboratory model. *Resting VO2 refers to data obtained from mice at thermoneutrality (∼30°C) and humans at room temperature (∼21–22°C). ** Mild cold VO2 refers to data obtained from mice at 21°C and humans at 18°C using a liquid conditioned suit, sufficient to induce a ∼2-fold increase in metabolic rate. Values in italics for mouse BAT tissue VO2, indicate that values are estimates calculated from the difference in whole-body oxygen consumption between NE-stimulated and unstimulated state and do not reflect actual tissue-specific in vivo measures of oxygen consumption. Others [6] have estimated the relative contribution of BAT to cold-induced thermogenesis in rats using radioactive microspheres to measure the fractional distribution of cardiac output/based on changes in tissue blood flow, which does not account for the oxygen extraction rate. aData from mice exposed to 30°C and 21°C [206,207]; bData from mice exposed to 4°C[208]; cData from [209]; dData from [210]; eData obtained from UCP1-dependent NE-stimulated metabolic rate in warm-acclimated mice, to more closely resemble human BAT [206]; fData derived from difference between metabolic rate of pre vs. post CL-stimulation [211]; gData derived from ex vivo high-resolution tissue respiration [61]; hData derived from [212]; iData derived from [17,20,35]; jData derived from [213]; kData derived from [214]; lData derived from [130]; mData derived from cold-exposed men [73]; nData derived from cold-exposed women [215]; oData derived from cold-exposed women [129]; pData derived from cold-exposed women [74].

Figure 4.
Mouse and human cold-induced whole-body and BAT thermogenesis.

Mouse data represents data obtained from C57BL/6 mice, as it represents the most common laboratory model. *Resting VO2 refers to data obtained from mice at thermoneutrality (∼30°C) and humans at room temperature (∼21–22°C). ** Mild cold VO2 refers to data obtained from mice at 21°C and humans at 18°C using a liquid conditioned suit, sufficient to induce a ∼2-fold increase in metabolic rate. Values in italics for mouse BAT tissue VO2, indicate that values are estimates calculated from the difference in whole-body oxygen consumption between NE-stimulated and unstimulated state and do not reflect actual tissue-specific in vivo measures of oxygen consumption. Others [6] have estimated the relative contribution of BAT to cold-induced thermogenesis in rats using radioactive microspheres to measure the fractional distribution of cardiac output/based on changes in tissue blood flow, which does not account for the oxygen extraction rate. aData from mice exposed to 30°C and 21°C [206,207]; bData from mice exposed to 4°C[208]; cData from [209]; dData from [210]; eData obtained from UCP1-dependent NE-stimulated metabolic rate in warm-acclimated mice, to more closely resemble human BAT [206]; fData derived from difference between metabolic rate of pre vs. post CL-stimulation [211]; gData derived from ex vivo high-resolution tissue respiration [61]; hData derived from [212]; iData derived from [17,20,35]; jData derived from [213]; kData derived from [214]; lData derived from [130]; mData derived from cold-exposed men [73]; nData derived from cold-exposed women [215]; oData derived from cold-exposed women [129]; pData derived from cold-exposed women [74].

Tissue thermogenesis

Quantifying BAT tissue oxidative metabolism and its relative contribution to whole-body energy expenditure has been of great interest to investigators since the discovery of BAT in humans many decades ago. Several approaches have been used to arrive to such estimates, be it by quantifying: (1) whole-body changes in energy expenditure in response to NE or ephedrine administration using indirect calorimetry; (2) changes in the relative distribution of cardiac output and hence tissue blood flow using radioactive microsphere [6] or 133Xe-clearance methods [218]; (3) changes in local temperature upon various stimulations using thermocouples, thermistors or thermography [10,219]; (4) changes in blood flow with changes in local temperature [218] or oxygen saturation [158], and more recently; (5) tissue oxygen consumption using PET/CT with [15O]O2 and [15O]H2O [128–130,157]. Of these, the latter is the only method to provide direct in vivo quantification of human BAT thermogenesis. At room temperature, BAT oxidative metabolism in humans has been reported to be 0.7–1.0 ml of O2·100 g of tissue−1 min−1 and increase to 1.2–1.4 ml of O2·100 g of tissue−1 min−1 under mild cold exposure [129,130,157] (Figure 4). If we assume a BAT volume of 50–150 g, this accounts for 0.1–0.4% of cold-induced whole-body oxygen consumption in men and 0.2–0.6% in women (Figure 4). This is in contrast with BAT accounting for 38–60% of cold-induced oxygen consumption in mice exposed to a mild cold (21°C) (Figure 4) [6,206,211]. Four weeks of daily cold exposure in humans can further increase BAT mass by 40–45% [20] and its oxidative capacity by 150% [73], which would theoretically increase the relative thermogenic contribution of BAT to account for 0.5–1.4% of whole-body oxygen consumption in men and 0.8–2.3% in women.

The ingestion of a carbohydrate-rich meal appears to also provide an adequate stimulus to increase BAT oxidative metabolism in humans, reaching levels observed during an acute mild cold exposure [157]. This provides evidence that: (1) stimulated human BAT may act as an energy sink, a function typically observed in mice to defend against diet-induced obesity [220], and; (2) that perhaps there is not a graded response to BAT stimulation, but is rather rapidly turned ‘on-off’ according to the presence or absence of sympathetic tone. It remains unclear whether pharmacological BAT stimulation in humans, through the administration of β-AR agonists or sympathomimetics, can increase oxidative metabolism [144,216,217,221,222]. Although some of these studies have demonstrated changes in the accumulation of [18F]FDG in BAT in response to β-AR agonists or sympathomimetics, [18F]FDG uptake has repeatedly been shown to be influenced by intracellular triglyceride content and closely coupled to tissue blood flow but not always to thermogenesis in humans (e.g. [13,35,127,149] and described below).

As an alternative to in vivo measures, estimates of tissue, cell or isolated mitochondria respiration have been reported from biopsied BAT tissue and in vitro differentiated primary human brown adipocytes under various stimulations [61,63,223]. However, these results often differ substantially from values obtained in vivo (see Figure 4) and are accompanied by certain caveats. One very significant caveat became apparent upon the discovery that BAT harvested from mice present subpopulations of mitochondria, some that are bound to lipid droplets (known as peridroplet mitochondria) and others that are unbound within the cytoplasm, with distinct protein compositions, bioenergetics and dynamics [224]. In particular, the peridroplet mitochondria, which are often discarded with the lipid fraction under some mitochondrial isolation procedures, appear to differ substantially in function compared with unbound cytoplasmic mitochondria. As the authors highlight, this raises important questions about the interpretation of past and future experiments performed on isolated mitochondria.

Energy substrate utilization

With [18F]FDG PET/CT being the most accessible tool to study human BAT in vivo, it is no surprise that much of what is known about this tissue to date relates to its accumulation of glucose. However, the use of other PET tracers and more invasive methods have provided valuable insight into how human BAT takes up and metabolizes other circulating substrates as well as its primary fuel source, intracellular TG (comprehensively reviewed [80]).

Glucose

As mentioned, much of what is known regarding human BAT relates to its accumulation of [18F]FDG under cold, postprandial or pharmacological stimulation. The use of static [18F]FDG PET/CT imaging has presented some significant challenges in understanding the relative importance of BAT in the clearance of circulating glucose. For example, although many research groups have taken careful precautions to limit shivering activity during their mild cold exposure protocols, the inability to visually detect the preferentially recruited deep muscle groups [179] or muscles shivering at a high frequency will result in a significant proportion of the [18F]FDG likely to accumulate there rather than BAT. In addition, the accumulation of [18F]FDG in BAT is significantly lower in individuals with obesity with or without type 2 diabetes (T2D), who have higher intracellular lipid content, yet present normal BAT oxidative metabolism and fatty acid uptake [13]. This has led many to argue that individuals with obesity and T2D have smaller ‘BAT volume’, whereas the accumulation of [18F]FDG in BAT is impaired in this population which will invariably lead to a significant underestimation of the true ‘BAT volume’ and certainly suggests that its capacity to significantly impact systemic glucose clearance is also impaired.

Dynamic [18F]FDG PET/CT imaging has allowed for the precise quantification of the rate of glucose uptake in human BAT. We previously reported that BAT glucose uptake rates during a mild cold exposure in fasted unacclimated men is in the range of ∼80 nmol g−1 min−1 [17,20,179] (Figure 4) and increases to ∼209 nmol g−1 min−1 following four weeks of daily cold exposure [20]. This is within the same range as has been reported by other investigators using dynamic [18F]FDG PET/CT, who have reported BAT glucose uptake rates of 90–120 nmol g−1 min−1 in healthy individuals [11,127,149], or using microdialysis across the supraclavicular BAT depot, who reported rates somewhat higher at ∼180 nmol g−1 min−1 [76]. In individuals with obesity or T2D, the rates of BAT glucose uptake falls to ∼35 nmol g−1 min−1 [127] and ∼10 nmol g−1 min−1 [13], respectively. By combining stable isotope methodologies with [18F]FDG PET/CT, we estimated that in healthy individuals the clearance of circulating glucose by BAT accounts for <1% of systemic whole-body glucose turnover [179]. While BAT glucose uptake rates per volume of tissue are two to three-fold greater than skeletal muscle, its relatively small size results in a relatively minor contribution to whole-body glucose turnover when compared with skeletal muscles, which account for ∼50% of glucose clearance. BAT glucose uptake has often been argued to be a reliable surrogate measure of BAT thermogenesis; however, the true metabolic fate of glucose once taken up by BAT remains uncertain and appears to be uncoupled to BAT thermogenesis. Studies performed in rats suggest that a significant proportion of glucose taken up by BAT is metabolized and released as lactate [225], which would certainly be consistent with the increased lactate release observed using microdialysis through human supraclavicular BAT [76]. This data suggests that as much as ∼50% of glucose taken up by human BAT may be released as lactate, given the limited stored glycogen in BAT. Other have shown, using human multipotent adipose-derived stem cells differentiated to brown adipocytes, that glucose is directed toward glyceroneogenesis [226], which would also be consistent with the increased requirement of glycerol given the increased glycerol release from cold-stimulated human BAT previously reported [76]. Clearly, further work is needed to clarify the metabolic fate of glucose in human BAT.

NEFA + triglyceride-rich lipoproteins (rate of uptake, metabolic fate, impact on whole-body)

The systemic availability of fatty acids is provided primarily from (1) NEFA mobilized following SNS-triggered lipolysis of intracellular TG in WAT; (2) ‘Spillover’ of fatty acids into the systemic circulation following lipoprotein lipase (LPL)-mediated lipolysis of TRL by WAT, and; (3) local tissue LPL-mediated lipolysis of TRL, thereby providing a localized supply of fatty acids. Using the LCFA PET analog [18F]FTHA, two groups have investigated BAT-specific fatty acid uptake rates under fasted and postprandial conditions. We and others have reported BAT fatty acid uptake rates in healthy, fasted, cold-exposed individuals of ∼13 nmol g−1 min−1 [13,17,130,157] (Figure 4), accounting for <0.1% of whole-body fatty acid turnover. This is nearly double the rate observed at room temperature (∼8 nmol g−1− min−1) and four times the rate observed by WAT both at room temperature and under cold stimulation (∼3 nmol g−1 min−1) [130]. Meal-induced SNS stimulation leads to significant fall in BAT NEFA uptake rates to ∼2.5 nmol g−1 min−1 [157], which is expected given the insulin-mediated suppression in WAT lipolysis and the increased delivery of fatty acids derived from TRL-TG. As circulating NEFA are taken up by human BAT at a significantly lower rate relative to glucose, it may be that NEFA are a less relevant fuel source for human BAT, at least during an acute mild cold exposure of a short duration. Whether circulating fatty acids are taken up at a more rapid rate during more prolonged exposure or following repeated cold exposures, remains to be determined. Certainly, in rodents, BAT fatty acid uptake rates increase progressively as the duration of the cold exposure is prolonged from 2 to 6 h and increases even further following a 21-day cold acclimation protocol [34]. Interestingly, human BAT fatty acid uptake rates do not appear to be influenced by obesity or the presence of T2D, both at room temperature and under cold stimulation [13,227].

A series of studies performed in rodents has suggested that TRL-triglyceride-derived fatty acids are the primary fuel source for BAT under cold stimulation and β3-AR agonism [161–163]. Using a novel PET/CT method developed at the Université de Sherbrooke, [18F]FTHA is administered orally, rather than by intravenous injection, to quantify organ-specific dietary fatty acid uptake and partitioning between organs [87]. Using this method, the orally administered [18F]FTHA reaches the circulation packaged largely within chylomicron TG, is taken up by most tissues and is later recirculated in the form of NEFA by WAT (following WAT ‘spillover’) and VLDL TG by the liver [87]. In cold-stimulated human BAT, dietary fatty acids are taken up at a rate that is two- to three-fold higher than cervical subcutaneous WAT and skeletal muscle per gram of tissue. However, due to the limited ‘BAT volume’ this only accounts for 0.3% of whole-body dietary fatty acid clearance, contrasting with skeletal muscle and the liver accounting for 50% and 24%, respectively [73]. Interestingly, four weeks of daily cold exposure increased BAT oxidative metabolism nearly three-fold yet had no effect on the rate of BAT DFA uptake. As mentioned above, the variable latency with which the orally administrated [18F]FTHA transforms and remains in relatively inaccessible compartments combined with the dynamic nature of TRLs limit the inferences that can be made and the ability to compare to the rodents studies where TRL-like particles were intravenously injected.

Several groups have reported associations between [18F]FDG PET-determined ‘BAT volume’ and whole-body lipid metabolism and glucose control [71,228–230], which they argue points towards BAT playing a significant role in lipid and glucose regulation. While there is no denying the remarkable rate with which human BAT can take up circulating glucose, NEFA or TRL-derived fatty acids, as determined directly using dynamic PET acquisition with [18F]FDG or [18F]FTHA, its relative size restricts its ability to significantly contribute to whole-body substrate clearance. Indeed, using PET with classical stable isotope methods, we have estimated that human BAT contributes <1%, <0.1% and <0.5% of whole-body glucose, NEFA and TRL-triglyceride-derived FA clearance, respectively, in cold-stimulated men. Consequently, efforts should be focused towards: (1) identifying mechanisms to increase BAT volume in humans; (2) attempting to understand the metabolic fate of these circulating substrates once taken up by the tissue, and; (3) how these substrates contribute to the replenishment of intracellular TG, which appear to be the primary fuel source for BAT.

Intracellular triglycerides

Under relatively short (2–3 h) acute cold exposures, intracellular TG in human BAT appears to be the predominant fuel source, whether participants are cold-acclimated vs. unacclimated [20,35,73], or whether fasted vs. fed [73]. Indeed, the administration of nicotinic acid to inhibit the hydrolysis of intracellular TG, suppresses BAT oxidative metabolism to levels seen at room temperature [35]. Although evidence in rodents suggests that suppressing whole-body fatty acid supply can indirectly impact BAT thermogenesis by impairing cardiac function [231], such a hypothesis appears unlikely in humans as there was still an adequate supply of fatty acids to meet the energetic demands and cold induces bradycardia [13], rather than the tachycardia response in rodents. With human BAT thermogenesis producing heat at a rate of 0.17–0.51 kcal h−1, assuming a ‘BAT volume’ between 50 and 150 ml, the energetic equivalent of the [18F]FDG taken up at a rate of ∼80 nmol g−1 min−1 (equivalent to 0.17–0.52 kcal h−1) and [18F]FTHA taken up at a rate of ∼13 nmol g−1 min−1 (equivalent to 0.11–0.27 kcal h−1), if oxidized completely, could theoretically account for all of the fuel to support this thermogenesis (∼0.28–0.79 kcal h−1). However, studies performed using microdialysis suggest that as much as ∼50% of glucose taken up by human BAT may be released as lactate [76] and a large proportion of the remaining glucose is likely directed towards glyceroneogenesis [226]. Consequently, in a fasted state, circulating NEFA may contribute ∼50–64% of the total fuel required for thermogenesis, whereas the remainder must be derived from intracellular TG. Data obtained from this same study using microdialysis, report that cold-stimulated BAT releases glycerol at a rate of 11 nmol g−1 min−1. The complete hydrolysis of a triglyceride molecule releases three fatty acids per molecule of glycerol, which suggests that the rate of fatty acid release following intracellular triglyceride lipolysis is ∼33 nmol g−1 min−1, amounting to ∼0.24–0.73 kcal h−1 of energy if all these fatty acids are directed towards oxidation. However, in contrast with WAT, BAT expresses high amounts of glycerol kinase [76,232], the enzyme required to form the carbon backbone of a triglyceride molecule, which allows some glycerol to be recycled within brown adipocytes rather than being released into the circulation. This would suggest that perhaps the BAT-derived systemic appearance of glycerol is likely an underestimation of the rate of BAT lipolysis. Collectively, these studies provide valuable evidence that BAT intracellular TG are the predominant fuel source to support thermogenesis. However, significant gaps remain in understanding the metabolic fate of fatty acids released from intracellular lipolysis and taken up by BAT from the circulation and their respective contributions to thermogenesis.

Clinical relevance of human BAT thermogenesis

There are two prevailing perspectives often used to describe the function and clinical relevance of human BAT. The first argues that the primary role of BAT is as a thermogenic organ, to produce the necessary heat to defend body temperature in newborn infants [233,234] and to preserve the functionality of vital organs during extreme or prolonged cold stimulations. The second, and certainly most common view, contends that BAT plays a critical role in weight management and whole-body energy metabolism by dissipating excess energy, thereby preventing diet-induced obesity and the development of its associated metabolic complications [235,236]. While current data certainly supports the argument for BAT playing a role in defending body temperature early in life and protecting vital organs, its role in weight management per se remains less convincing. First, whereas, the prevalence of both T2D and gestational diabetes rises with increases in mean annual outdoor temperature [237,238], when BAT would presumably be less active, obesity prevalence is not associated with outdoor temperature [237]. Second, from prospective investigations, several metabolic benefits have been ascribed to the stimulation of human BAT thermogenesis, including protecting from the development of obesity [235,236], as well as improving glucose regulation [229,236] and lipid metabolism [217,228,239]. However, these findings are based on associations, with direct measures identifying the causal links with BAT still lacking. Indeed, studies exposing participants to a daily cold stimulus of various durations, frequencies, temperatures, cooling modalities and populations [20,71,73,74,236,240,241], reveal that such interventions do not lead to any changes in body weight (see [242] for review), despite increasing ‘BAT volume’ and oxidative capacity. The evidence from both epidemiological and intervention studies, therefore, raise several doubts about the clinical relevance of BAT for weight management.

The role of BAT in regulating glucose and lipid metabolism as well as insulin sensitivity remains a matter of contention. Cold exposure has been shown to reduce circulating glucose and insulin levels in individuals with T2D [13] and improve whole-body insulin sensitivity following 10-days of daily cold exposure in individuals with obesity and T2D [236,243]. However, the latter was attributed to a cold-induced increase in total GLUT4 protein content and translocation to the cell membrane in skeletal muscle. Using a pharmacological stimulus to target BAT, healthy, young women given a daily oral 100 mg dose of the β3-AR agonist mirabegron for 4 weeks increased ‘BAT volume’ and was accompanied by an increase in circulating HDL and adiponectin levels and improved insulin sensitivity [217]. The increased accumulation of glucose in BAT in response to this intervention certainly suggests that it could have contributed to the improved insulin sensitivity. However, such high doses also increase heart rate, systolic blood pressure and NEFA circulating levels, which would be consistent with off-target binding to the β1- and β2-AR, thereby precluding the ability to directly link the increased ‘BAT volume’ to the reported metabolic improvements.

Together, these findings lead to further questions about the potential clinical relevance of human BAT, particularly in the context of weight management, whole-body energy homeostasis and improving whole-body insulin sensitivity. Although it appears unlikely that human BAT thermogenesis can contribute meaningfully to weight management, it does display tremendous potential as a metabolic sink to protect against a surplus of fatty acids and glucose and improve insulin sensitivity. The role of BAT in substrate clearance and utilization likely has meaningful local effects to protect lean organs from an overexposure of substrates but may not necessarily result in whole-body changes in energy metabolism. The question is how much BAT and what magnitude and frequency of thermogenesis would be required for weight maintenance or to elicit clinically relevant changes in glycemia, insulinemia and triglyceridemia in humans and can it be accomplished pharmaceutically? Does BAT contribute directly to this metabolic regulation or act more as an endocrine organ? Would a stimulation in BAT thermogenesis also be accompanied by an increase in energy intake thereby counteracting the potential benefits of thermogenesis? These are some of the many critical questions that remain to be answered before we can fully establish its clinical relevance in humans.

Conclusions

Since the release of the three seminal papers published in the New England Journal of Medicine in 2009, there has been tremendous progress in the in vivo functional characterization of human BAT. While earlier studies focused on characterizing the biomolecular features of BAT and inferring from that its function, the advent and ubiquity of PET and MRI imaging centers has extended those observations into in vivo functional assessments. [18F]FDG PET/CT has been the most commonly used tool to assess human ‘BAT volume’ and metabolic activity, in part thanks to its reliability in spontaneously detecting BAT in unstimulated individuals. However, being a glucose analog designed to assess glycolytic tissues, its practicality in studying a highly oxidative tissue has proven to be somewhat problematic and has demonstrated its limitations. This has led to the development of several other PET and MRI-based methods to investigate the role of BAT in clearing circulating fatty acids derived from WAT or carried by TRL, its oxidative capacity, perfusion and reliance on intracellular TG to fuel thermogenesis. These tools have proven to be useful in studying the function of BAT in aging, metabolic disorders, regulating circadian temperature and glycemic rhythms, its acute response and plasticity in the face of various environmental and pharmacological stimuli, while also bringing to light significant gaps that remain in the field. Most notably, several critical questions remain which concern the quantification of ‘BAT volume’, the metabolic fate of circulating glucose and NEFA taken up by BAT, as well as the fate of fatty acids released following intracellular triglyceride lipolysis, its impact on whole-body energy metabolism, its plasticity in response to various stressors, and most importantly whether its anatomical locations predict its local function. Further work is required to continue building the tools to investigate these questions in vivo in humans. This is particularly important to better understand the unique function of this highly specialized heat-generating tissue, in a non-hibernator reliant on external heat sources to maintain a thermal balance.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Acknowledgements

D.P. Blondin is the recipient of the GSK Chair in Diabetes of the Université de Sherbrooke. Original work from our group in the field of human brown adipose tissue metabolism has been funded by grants from the Canadian Diabetes Association, the Canadian Institutes of Health Research (grant no. 299962) and the Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-05291). Work in this laboratory is currently funded by the Natural Sciences and Engineering Research Council of Canada (RGPIN-2019-05813). MAR is supported by a scholarship from the Natural Sciences and Engineering Research Council of Canada (CGS D). H. Pallubinsky was supported by travel fellowships provided by the European Federation for the Study of Diabetes (Albert Renold Travel Fellowship), the Netherlands Royal Academy for Arts and Sciences (KNAW van Leersum Travel Grant) and the Netherlands Cardiovascular Research Initiative: an initiative with the support of the Dutch Heart Foundation (CVON2014-02 ENERGISE Building Bridges Travel Fellowship).

Abbreviations

     
  • BAT

    brown adipose tissue

  •  
  • CT

    computed tomography

  •  
  • LCFA

    long-chain fatty acids

  •  
  • LPL

    lipoprotein lipase

  •  
  • MRI

    magnetic resonance imaging

  •  
  • MRS

    magnetic resonance spectroscopy

  •  
  • NE

    norepinephrine

  •  
  • NIRS

    near-infrared spatially resolved spectroscopy

  •  
  • NMR

    nuclear magnetic resonance

  •  
  • PET

    positron emission tomography

  •  
  • SNS

    sympathetic nervous system

  •  
  • SPECT

    single-photon emission computed tomography

  •  
  • SUV

    standard uptake value

  •  
  • T2D

    type 2 diabetes

  •  
  • TG

    triglycerides

  •  
  • TRL

    triglyceride-rich lipoproteins

  •  
  • UCP1

    uncoupling protein 1

  •  
  • WAT

    white adipose tissue

  •  
  • β-AR

    β-adrenergic receptors

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