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Manuscript Number: DIABET-D-17-00036R1
Title: A Synopsis of Brown Adipose Tissue Imaging Modalities for Clinical
Research
Article Type: Review
Keywords: Brown adipose tissue, Clinical Imaging, Non-invasive, Obesity
Corresponding Author: Dr. Lijuan Sun, Ph.D
Corresponding Author's Institution: Singapore Institute for Clinical
Sciences
First Author: Lijuan Sun, Ph.D
Order of Authors: Lijuan Sun, Ph.D; Jianhua Yan; Lei Sun; S. Sendhil
Velan; Melvin Leow
Manuscript Region of Origin: SINGAPORE
Abstract: Body weight gain results from a chronic excess of energy intake
over energy expenditure. Accentuating endogenous energy expenditure has
been accorded much attention since the recognition of the existence of
brown adipose tissue (BAT) in adult humans, given that BAT is known to
increase energy expenditure via thermogenesis. Besides classical BAT,
significant strides in the understanding of inducible brown adipocytes
have been made in terms of its development and function. While it is
ideal to study BAT histologically, its relatively inaccessible anatomical
locations and the inherent risks associated with biopsies preclude
invasive techniques to evaluate BAT on a routine basis. Hence, there is a
surge in interest to employ non-invasive methods to examine BAT. The gold
standard for the non-invasive detection of BAT activation is 18-
fluorodeoxyglucose positron emission tomography with computerized
tomography (PET/CT). However, the major limitation of PET/CT as a tool
for BAT studies in humans is the exposure to clinically significant doses
of ionizing radiation. In more recent years, several other imaging
methods including single-photon emission computed tomography (SPECT/CT),
magnetic resonance imaging (MRI), infrared thermography/thermal imaging
(IRT) and contrast ultrasound (US) have been developed with the hope that
these will allow non-invasive, quantitative measures of BAT mass and
activity at lower costs. This review focuses on methods to detect human
BAT activation and white adipose tissue (WAT) browning that will catalyse
the establishment of BAT-centric strategies to augment energy expenditure
and combat obesity. Validation of these methods in human will likely
expand the scope and flexibility of future BAT studies.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
1
A Synopsis of Brown Adipose Tissue Imaging Modalities for Clinical Research 1
Lijuan Sun1#
, Jianhua Yan2,3#
, Lei Sun4, S. Sendhil Velan
5, 6, Melvin Khee-Shing Leow
1, 6, 7,8,9,10,11* 2
1. Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), 3 Agency for Science, Technology and Research (A*STAR) and National University Health 4 System, Singapore 5
2. Department of Nuclear Medicine, First Hospital of Shanxi Medical University, China 6 3. Molecular Imaging Precision Medicine Collaborative Innovation Center, Shanxi Medical 7
University, China 8
4. Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 9
5. Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, A*STAR, Singapore 10
6. Departments of Medicine and Physiology, Yong Loo Lin School of Medicine, National 11
University of Singapore 12
7. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 13
8. Office of Clinical Sciences, Duke-NUS Medical School, Singapore 14
9. Clinical Trials and Research Unit, Changi General Hospital, Singapore 15
10. Department of Medicine, National University Hospital, Singapore 16
11. Department of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore 17
18
#Lijuan Sun and Jianhua Yan contributed equally to this article as the co-first authors. 19
*Correspondence should be addressed to: 20
Melvin Khee-Shing Leow, MD 21
Centre for Translational Medicine, 14 Medical Drive #07-02, MD 6 Building, Yong Loo Lin School of 22
Medicine, Singapore 117599 23
Tel: +65 6407 0105 24
Fax: +65 6774 7134 25
Email: [email protected] 26
27
Conflict of interest statement: 28
All authors declare no conflict of interest. 29
Number of tables: 1 30
Figure: 7 31
32
33
*Manuscript
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2
Abstract: 34
Body weight gain results from a chronic excess of energy intake over energy expenditure. 35
Accentuating endogenous energy expenditure has been accorded much attention since the 36
recognition of the existence of brown adipose tissue (BAT) in adult humans, given that BAT is known 37
to increase energy expenditure via thermogenesis. Besides classical BAT, significant strides in the 38
understanding of inducible brown adipocytes have been made in terms of its development and 39
function. While it is ideal to study BAT histologically, its relatively inaccessible anatomical locations 40
and the inherent risks associated with biopsies preclude invasive techniques to evaluate BAT on a 41
routine basis. Hence, there is a surge in interest to employ non-invasive methods to examine BAT. 42
The gold standard for the non-invasive detection of BAT activation is 18-fluorodeoxyglucose positron 43
emission tomography with computerized tomography (PET/CT). However, the major limitation of 44
PET/CT as a tool for BAT studies in humans is the exposure to clinically significant doses of ionizing 45
radiation. In more recent years, several other imaging methods including single-photon emission 46
computed tomography (SPECT/CT), magnetic resonance imaging (MRI), infrared 47
thermography/thermal imaging (IRT) and contrast ultrasound (US) have been developed with the 48
hope that these will allow non-invasive, quantitative measures of BAT mass and activity at lower costs. 49
This review focuses on methods to detect human BAT activation and white adipose tissue (WAT) 50
browning that will catalyse the establishment of BAT-centric strategies to augment energy expenditure 51
and combat obesity. Validation of these methods in human will likely expand the scope and flexibility 52
of future BAT studies. 53
Keywords: Brown adipose tissue, Clinical Imaging, Non-invasive, Obesity 54
55
56
57
58
59
60
61
62
63
64
65
66
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3
Introduction 67
Obesity is a global epidemic associated with debilitating metabolic and cardiovascular sequelae 68
including diabetes, hypertension and dyslipidemia. A fundamental basis for the obesity crisis is a 69
surplus of energy intake over energy expenditure. Excess calories are stored preferentially as 70
triglycerides in WAT (white adipose tissue), an evolutionarily conserved adaptation in the light of the 71
maximum energy density of fat for tissue storage space economy. WAT is an energy-storing tissue, 72
whereas BAT dissipates energy in the form of heat. Indeed, the thermoregulatory function of BAT in 73
small and hibernating mammals including human neonates and infants has been known for decades 74
[1, 2]. Beyond survival advantage conferred by this adaptive process, overwhelming evidences that 75
BAT activation can improve whole body metabolism [3-5] brought about a resurgence in research 76
interest on BAT, ever since it was demonstrated to exist in human adults by 18
F-fluorodeoxyglucose 77
(18
F-FDG) positron emission tomography with computerized tomography (PET/CT)in 2002 [6]. Recent 78
evidence has also described the existence of brown adipocyte-like cells within WAT which harbour 79
similar phenotype to BAT called beige or brite (ie. ‘brown in white’) adipocytes in distinction from 80
“classical constitutive BAT“[7]. As both classical brown and beige/brite adipocytes are thermogenic 81
and expend stored energy, they add to the expanding arsenal against obesity and diabetes [8]. There 82
are many excellent reviews on BAT biology and its catabolic processes [9-11], whereas the present 83
review focuses on the methodology for imaging BAT activation and WAT browning with an emphasis 84
on human applications and highlights the advantages and drawbacks of each method. 85
86
BAT characteristics and WAT browning 87
Classical brown adipocytes reside in depots of infants anatomically localized to the interscapular, 88
supraclavicular, pericardial, suprarenal and paraaortic regions. “Beige” or ‘brite” adipocytes in human 89
adults can be found in fat tissue in the neck, supraclavicular areas, mediastinum (para-aortic), 90
paravertebral and suprarenal regions. Supraclavicular and cervical BAT constitutes the two most 91
abundant and readily inducible depots in most persons examined[12]. Here, BAT is predominantly 92
composed of inducible beige/brite adipocytes[9]. BAT prevalence and activity have been 93
demonstrated to correlate negatively with age, body mass index, diabetes status and outdoor 94
temperatures [13, 14]. BAT is thought to be present in the majority of, if not all, adult humans though 95
its ‘activatable’ property within any given person remains questionable [15]. Cold and diet-induced 96
thermogenesis are both mediated by BAT. Activated BAT preferentially oxidises lipids for fuel though 97
it also utilises glucose as a metabolic substrate. BAT might thus be exploited therapeutically for its 98
anti-obesity, lipid and glucose-lowering effects [3, 16]. 99
BAT biopsy is the definitive method for identifying histologic features of brown adipocytes and 100
distinguishing it from WAT. Morphologically, brown adipocytes are characterized by their numerous 101
small lipid droplets, polygonal shape, smaller size, iron-containing mitochondria in significantly higher 102
numbers responsible for the brownish colours opposed to white adipocytes[17]. BAT has a 103
remarkably higher density of sympathetic innervation compared to WAT[14]. 104
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4
The 32 kDa uncoupling protein 1 (UCP1) - a long chain fatty acid-activated protein, known as 105
thermogenin, is the sine qua non attribute characterising the heat-dissipating mitochondria of BAT. 106
UCP1 sits in the inner mitochondrial membrane and behaves as a protonophore by facilitating proton 107
leak from the intermembrane space back to the mitochondrial matrix which physiologically uncouples 108
the respiratory chain and releases energy as heat instead of ATP biosynthesis-a process known as 109
adaptive thermogenesis [18]. UCP1 thus increases fuel oxidation, independent of intracellular levels 110
of ATP and generates a remarkable thermal power to the order of 300 W/kg in rodents 111
experiments[19]. If extrapolated to humans, approximately 50 g of BAT can account for up to 20% of 112
total energy expenditure [20] while nearly 4 kg weight loss over the course of a year has been 113
estimated to occur with roughly 60 g of BAT in human PET studies [21]. 114
White adipose tissue (WAT) under the appropriate stimuli has the capacity of transforming into 115
inducible brown adipose tissue (termed beige or brite fat). Notably, this “browning” of WAT may 116
occur through differentiation of adipocyte stem cells residing within WAT towards a beige 117
phenotype [22] or via a more controversial process of trans-differentiation of white into brown 118
adipocytes [23]. Browning of white adipose is often observed in mouse models, but not in human. 119
Recently, Labros and his colleague reported that human subcutaneous white adipose tissue (sWAT) 120
can transform from an energy-storing to an energy-dissipating tissue after severe adrenergic stress 121
which demonstrated that human sWAT exhibits the plasticity to undergo browning [24]. The molecular 122
pathways governing this browning process are still being unravelled while established intracellular 123
signals include the following. Peroxisome-proliferator–activated receptor γ (PPAR- γ) coactivator-1 α 124
(PGC-1α) is the key regulator of mitochondrial biogenesis and oxidative metabolism [25]. In humans, 125
PGC1-α mRNA expression is highly expressed in BAT relative to WAT [26] which correlates with the 126
higher energy production rate of BAT [27]. PGC1-α is not only enriched in both classical BAT depots 127
but its expression also can be induced in beige/brite adipocytes by cold exposure [28] By inducing the 128
expression of UCP1, PGC-1α is a master regulator of brown adipogenesis. 129
PR domain-containing protein-16 (PRDM16) had been identified to specifically enrich in classical 130
brown fat relative to WAT [29]. PRDM16 was demonstrated to play an important role in promoting 131
browning in visceral fat under β-adrenergic stimulation [29]. Ectopic expression of PRDM16 in WAT 132
induced brown adipocyte specific gene expression including UCP1 and PGC-1α complemented by an 133
increase in mitochondrial volume and oxygen consumption [29]. PRDM16 abundance is significantly 134
higher in supraclavicular BAT than WAT in humans [26]. 135
Browning of WAT can theoretically be harnessed as a strategy for obesity treatment if the stimuli to 136
recruit and activate beige adipocytes from white adipocytes are safe and efficacious. There are 137
several stimuli that can increase BAT activity including cold exposure, β-adrenergic receptor agonists 138
and other pharmacological agents that may be used in conjunction with PET imaging studies. PPAR 139
Ƴ activators, thiazolidinediones can recruit BAT depots and facilitate the browning of WAT [30, 31]. In 140
recent years, there are many novel nonadrenergic soluble molecules which have been identified to be 141
capable of inducing the browning of WAT[32]. These browning-inducing stimuli molecules are as 142
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5
summarized in Figure1. Cold exposure is the best and most widely used stimulus of BAT activity. 143
Subjects exposed to temperature between 16 ºC and 19 ºC for 1 to 2 hours have higher BAT-positive 144
detection rates [33, 34]; hence the same individuals can switch from BAT negative to positive status 145
and vice versa depending on various conditions. Numerous studies have also proven the positive 146
association between cold-activated BAT detected by PET/CT scans and energy expenditure [35-40]. 147
Women when exposed under 19 ºC for 12 hours as compared to 24 ºC ambient temperature showed 148
a 5% increase in energy expenditure [41]. An estimated 250 kcal/day energy expenditure increase 149
was observed among healthy young men exposed to 19 ºC for 2 hours [42]. 6 weeks (17 ºC for 2 150
hours /day) of chronic cold exposure was shown to increase 18
F-FDG uptake and energy expenditure 151
in subjects with absent or low 18
F-FDG at baseline PET/CT scans [42]. This result showed that BAT in 152
adult humans can either be activated or recruited to tackle obesity. 153
154
Positron Emission Tomography-Computed Tomography (PET/CT) imaging 155
PET/CT is now an important cancer imaging tool for staging, re-staging, treatment monitoring and 156
prognostication [43], surpassing over PET or CT alone and minimizes their individual limitations. 18
F-157
FDG is a glucose analog labelled with isotope 18-fluorine. Like glucose, 18
F-FDG can enter the cells 158
mediated by a group of structurally related glucose transport proteins (GLUT) and then is 159
phosphorylated by hexokinase as the first step toward glycolysis. In contrast to glucose, the 6-160
phosphate derivative of FDG cannot be further metabolised downstream for energy production and 161
thus remains trapped within the metabolically active cells [44]. Classic brown adipocytes express 162
high glucose transporter protein 1 and 4 and are therefore FDG positive [45]. Many studies have 163
suggested 18
F-FDG PET imaging as a reference to non-invasively identify BAT and depict metabolic 164
activity of BAT depots [26, 46] (Figure 2). With the help of CT or MR, the hot BAT depots could be 165
precisely located [12]. Virtanen et al [26] combined using 18
F-FDG PET/CT scan and biopsy 166
specimens of paracervical and supraclavicular tissue RNA and protein results confirmed the presence 167
of certain amounts of metabolically active brown adipose tissue in adults in 2009. In addition, women 168
were found to harbour had a greater mass of BAT brown adipose tissue and higher 18
F-FDG uptake 169
activity than men. Moreover, the amount of BAT brown adipose tissue was inversely correlated with 170
body mass index [47]. Since then, many researchers and clinicians started to investigate the 171
physiological characteristics of BAT using 18
F-FDG PET/CT as the dominant “gold standard” imaging 172
method. 173
Using 18
F-FDG PET/CT to study BAT prevalence and function in humans is however potentially 174
fraught with errors. Based on the early large retrospective reports, prevalence estimates of BAT in 175
humans from PET/CT ranged between 2% to 7% [13, 48]. The low prevalence reported casted doubt 176
on the physiological significance of BAT. According to the studies of multiple scans, the average 177
likelihood of getting another positive scan among patients with BAT is 13.3% [49]. Lee et al [15] 178
analysed the supraclavicular fat histologically in subjects who did not have elevated 18
F-FDG uptake 179
on PET/CT scans and found a predominance of cells with uniloculated lipid droplets, with scattered 180
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6
cells containing multiloculated lipid droplets and variable UCP1 immunostaining different from 181
subcutaneous WAT. In comparison with anatomical CT/MR, PET has limited spatial resolution 182
inducing partial volume effect and underestimation of tracer uptake. For example, only the uptake 183
within region of interest (ROI) with size greater than three times PET spatial resolution (typically 3~8 184
mm) could be accurately estimated [50, 51]. In addition, accurate delineation of ROI is a prerequisite 185
for quantification of tracer uptake, however, it is still a challenging task although many approaches 186
have been proposed [52]. Threshold method based on either fixed standardized uptake value (SUV) 187
or percentage of maximum SUV is most commonly used in BAT delineation in PET image. Because 188 18
F-FDG is mainly taken up in active BAT, any uptake below the threshold due to either small 189
quantities of BAT tissue or low levels of BAT activation would be classified as ‘BAT-negative’ even 190
though this may not necessarily connote the absence of BAT [53]. Therefore, conventional diagnostic 191 18
F-FDG PET/CT has limited accuracy and poor reproducibility with respect to BAT detection. This 192
may account for the underestimation of BAT prevalence especially under certain ambient conditions. 193
BAT activity is often estimated by using tracer uptake values which can have significant inter-194
individual differences between obese and lean subjects [53, 54]. Several factors including how to 195
define BAT positivity in PET images, threshold cut-offs for SUV, criteria for separating fat tissue using 196
CT etc have yet to be standardized which makes the quantification of BAT using PET/CT challenging. 197
Additionally, 18
F-FDG uptake can be affected by the activity of glucose transporters. It should be also 198
noted that the energy source for BAT is not restricted to glucose but also free fatty acids. Beyond 18
F-199
FDG, BAT could accumulate a range of tracers including 11
C-acetate and 18
F-fluoro-200
thiaheptadecanoic acid (18
F-THA) reflecting oxidative metabolism [55]. Moreover, oxygen 201
consumption by BAT could be indirectly measured via perfusion information provided by 15
O-H2O PET 202
imaging [56] or directly measured by 15
O-O2 PET imaging [37]. 18
F or 14
C fluorobenzyltriphenyl 203
phosphonium (FBnTP) is a probe which can accumulate in proportion to cellular membrane potential. 204
FBnTP PET accumulates in high levels in inactive BAT [57] but the signal decreases after BAT 205
activation. This is also true for 11
C-methylreboxetine (11
C-MRB), a PET tracer that labels sites of 206
sympathetic innervation. 11
C-MRB PET preferentially accumulates in inactive BAT with minimal 207
increase in signal after BAT activation. Although PET/CT offers exceptional sensitivity in detecting 208
active BAT, ionizing radiation of PET/CT, especially CT, limits its application on healthy volunteers for 209
clinical research. Both PET and CT bring radiation exposure to subjects. The radiation exposure from 210
CT has a very wide range depending on the type and the purpose of the test. Low dose non-211
diagnostic CT protocol (for example, 120 kVp and 50 mAs) is used for whole body PET/CT scan, 212
which approximately equals to 5 mSv. The amount of injected dose of 18
F-FDG depends on subject’s 213
weight. The typical dose of 18
F-FDG for an 80 kg subject is 315 MBq and the corresponding radiation 214
exposure is about 6 mSv. Thus, the typical radiation exposure from a whole body PET/CT scan is 215
around 10 mSv, which is 100 times more than that of a chest X-ray. Combined positron emission 216
tomography/magnetic resonance (PET/MR) scanner is being increasingly used in the clinics and 217
research centres and is a great alternative to PET/CT for BAT and WAT imaging without CT ionizing 218
radiation [58] In addition, MR imaging is an ideal imaging for the evaluation of body fat due to its 219
outstanding spatial resolution and detailed soft-tissue characterization. 220
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7
221
Single-photon emission computed tomography/CT (SPECT/CT) imaging 222
Cold-stimulated BAT activation is mainly mediated by norepinephrine released from the sympathetic 223
nervous system (SNS) and norepinephrine can interact with β-adrenergic receptors to stimulate 224
thermogenesis [12, 45]. SNS-induced BAT stimulation can be visualized using single-photon emission 225
computed tomography/CT (SPECT/CT). SPECT is a three-dimensional functional nuclear medicine 226
tomographic imaging technique using gamma rays produced from a gamma-emitting radioisotope. 227
The emission intensity from the radioactive ligand is a function of the capillary blood flow and 228
metabolic status within the imaged tissue. With the help of CT information, the functional information 229
from SPECT could be anatomically correlated. 230
SPECT tracers available for clinical application include 123
I-meta-iodobenzylguanidine (123
I-MIBG), 231 99m
Tc-sestamibi, 99m
Tc-tetrofosmin. A few studies have reported that SPECT tracers such as 123
I-232
meta-iodobenzylguanidine (123
I-MIBG), 99m
Tc-sestamibi and 99m
Tc-tetrofosmin demonstrated similar 233
uptakes patterns with 18
F-FDG PET/CT scans for BAT [59-61]. 234
123I-MIBG is a radiolabeled norepinephrine analog, is used for scintigraphic assessment of 235
neuroendocrine tumors and cardiac sympathetic activity [62, 63]. For instance, 123
I-MIBG uptake was 236
found to be incidentally increased in the bilateral laterocervical areas consistent with BAT in a young 237
male underwent bilateral adrenalectomy [64]. A strong correlation has been found between 18
F-FDG 238
PET/CT and 123
I-MIBG SPECT/CT for detecting BAT after a cold stimulus in lean and obese young 239
men but not in older men confirming that 123
I-MIBG SPECT/CT is capable of detecting the SNS BAT 240
activity in both the lean young and obese subjects [65, 66] (Figure 3). In 2002, Okuyama et al. [67] 241
showed that 123
I-MIBG accumulated in the adrenergic nervous system in BAT in rats model. Gelfand 242
[68] demonstrated that 123
I-MIBG uptake was noted in the normal side of neck and shoulder regions 243
caused by uptake in BAT in a 3-year-old girl with neuroblastoma. In a retrospective [61] review of 266 244 123
I-MIBG scans for neuroendocrine tumors, accumulation in the nape of the neck was seen in 12% of 245
the scans which were not identified as tumor; these were thought to be related to the uptake in BAT. 246
Moreover, it has been proven that 123
I-MIBG SPECT/CT and 18
F-FDG PET/CT had strong correlation 247
to measure BAT activity and also identify the same anatomic regions as active BAT. This finding is 248
consistent with others and suggests that BAT activity in humans is influenced by the sympathetic 249
nervous system. 123
I-MIBG SPECT/CT was therefore identified as a tool to visualize and quantify the 250
sympathetic stimulation of BAT. The suggested activity of 123
I-MIBG administered to adults is 400 251
MBq for tumor imaging [69]. The corresponding absorbed dose at the thyroid is about 2.24 mGy and 252
the effective dose from 123
I-MIBG is 5.2 mSv. Usually, orally administered stable iodine is required to 253
prevent thyroid uptake of free iodine before 123
I-MIBG SPECT/CT scan. The oral administrations of 254
stable iodine was suggested to be initiated a day before the planned 123
I-MIBG injection and 255
maintained for 1-2 days [69]. 256
99mTc-sestamibi goes through the cell membrane by passive diffusion and is retained within the 257
mitochondria in the cell [70]. 99m
Tc-sestamibi uptake in BAT was higher compared to WAT and highly 258
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8
determined by body size as the BAT/WAT uptake ratio decreases with increasing body weight [71]. 259 99m
Tc-sestamibi uptake was increased in the activated BAT probably due to the abundant blood flow 260
and the high density of mitochondria in brown adipocytes [59]. Importantly, 99m
Tc-sestamibi can 261
accumulate in BAT of patients suffering from primary hyperparathyroidism which can potentially lead 262
to erroneous parathyroid adenoma localization due to false positives among such cases in clinical 263
practice [72, 73]. 264
Another tracer used in SPECT/CT is 99m
Tc-tetrofosmin whose uptake is dependent on the plasma 265
membrane and mitochondrial potential [74]. Kazuki et al [75] found a higher 99m
Tc-tetrofosmin uptake 266
rate in the interscapular BAT (17 % of the patients) compared to BAT imaging using 123
I-MIBG (10%) 267
or 18
F-FDG (2.5%–4.0%). Both 99m
Tc-tetrofosmin and 99m
Tc-sestamibi scintigraphy can image human 268
BAT distribution. 269
270
Magnetic resonance imaging (MRI) 271
Human BAT can also be detected by magnetic resonance imaging (MRI) because BAT has a high 272
intracellular and extracellular water content, resulting in higher water-to-fat ratio than WAT in humans, 273
increased iron content, large density of mitochondria and blood vessels in BAT resulting in lower T2 274
and T2* relaxation [76, 77] (Figure 4). Since MRI does not have ionizing radiation although it employs 275
non-ionizing radiofrequency pulses, it is more attractive and suitable for repeated measurements as a 276
BAT imaging modality in children and healthy populations. Fat fraction is significantly lower in BAT 277
than in WAT in infants, adolescents, and adult human subjects. A wide range of fat fraction values 278
across subjects was found in BAT (30-94%) but not in WAT (83-96%) using chemical-shift encoded 279
water-fat MRI [78]. One of the challenges for MRI measuring fat is overlapping fat fraction (FF) and 280
relaxation value between WAT and BAT. However, metabolic inactive BAT which could not detected 281
via 18
F-FDG PET/CT can be imaged using MRI under room temperature. This raises the potential 282
feasibility of MRI in identifying BAT independent of the tissue metabolic status, and supported the 283
notion that the visual absence of BAT FDG uptake does not necessarily imply its absence [79]. The 284
MRI- fat signal fraction of active BAT was significantly lower than that of inactive BAT [80]. Other 285
information derived from MRI like temperature, diffusion, perfusion could also differentiate BAT 286
without human subjectivity, independently of the activation status of BAT [80]. Chen et al [76] verified 287
that the location and volume of BAT deduced via MRI were comparable to the measurements by 18
F-288
FDG PET/CT scans under thermoneutral conditions. In addition, MRI showed a high BAT intra- and 289
inter-reliability for measuring BAT [77]. 290
Water-fat separation MRI method cannot differentiate active from inactive BAT under room 291
temperature whereas functional MRI can, such as described next. Blood-oxygen-level-dependent 292
(BOLD) MR imaging is based on the principle that increased oxygen consumption and blood flow 293
aligned with a change in the relative levels of oxy- and deoxy-hemoglobin produce a detectable 294
change in the intensity of the MR signal [81]. It is sensitive to localized oxygen consumption and blood 295
flow during activation of BAT. This approach has been exploited to detect activated BAT in rodents 296
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9
using T2 and T2* imaging [81]. BOLD contrast can also be used in MRI to detect BAT activity in a 297
mild cold stimulation [76]. It has been demonstrated that BOLD MRI identified a 10% change in BAT 298
signal intensity when exposed to cold compared to normal condition [76] which raises the possibility to 299
study BAT activation in dynamic studies using BOLD-based MR techniques. In addition, dynamic T2* 300
weighted imaging is another functional MRI capable of evaluating active BAT based on the BOLD 301
MRI technique. In a study of 11 healthy young subjects, dynamic T2* weighted imaging during cold 302
exposure revealed signal fluctuations that were sensitive to BAT activation. The presence of these 303
elements significantly correlated with BAT activation quantified from 18
F-FDG PET [78]. However, 304
there is a low specificity of measuring BAT activation using T2* weighted imaging. 305
Intermolecular multiple quantum coherences (iMQC’s) can be created using distant dipolar field and 306
utilized in imaging and spectroscopic measurements [82]. This technique permits modulation of 307
transverse magnetization with coherence selection gradients where the signal can be detected from 308
spins within a correlation distance d = π γ G t. This method has been extended to probe the spatial 309
correlation between fat and water spins at a cellular level in BAT and WAT using intermolecular zero-310
quantum coherences (i-ZQC’s) [83]. Using this approach i-ZQC spectrum of BAT shows a water – 311
methylene cross peak in BAT whereas it is absent in WAT and muscle tissues of rodents and also in 312
humans [84]. Chemical shift encoded Dixon based approach has been combined with intermolecular 313
double quantum coherences (i-DQC’s) to separate BAT from WAT signals[85]. 314
Hyperpolarized xenon gas based MR imaging has been demonstrated for investigating BAT in 315
rodents [86]. Inhaled hyperpolarized xenon gas is transported to lungs and other organs. The 316
dissolved gas accumulates in different tissues proportional to tissue perfusion rate. The highly 317
vascularized BAT shows a large xenon signal with activation [86]. 318
Active BAT expends thermal energy predominantly via fatty acid oxidation. Hence, it regulates 319
triglyceride-rich lipoproteins (TRL) and blood lipid abundance [16]. BAT activity can thus be measured 320
via real time MR imaging using superparamagnetic iron oxide nanocrystals (SPIO) which accelerate 321
spin-spin relaxations, embedded into TRL cores to follow lipoprotein uptake into the liver [87]. 322
MRI-based techniques have the potential ability of differentiating BAT from WAT and identifying 323
activated BAT from non-activated BAT without ionizing radiation, a clear advantage over PET/CT for 324
the study of human BAT. Capitalising upon the ability of PET to visualize metabolic processes in BAT 325
with a high sensitivity and the ability of MRI to visualize perfusion and intracellular properties (lipid 326
content, water content or even mitochondrial activity), the combined PET/MR fusion imaging device 327
facilitates the separation of activatable from inactivatable human BAT. Although BAT in pediatric 328
patients can be detected and discriminated from WAT by using MRI only, hybrid PET/MRI could 329
provide information about the composition and degree of BAT and its specific activation status [58]. 330
Infrared thermography imaging (IRT) 331
Thermal imaging camera detects infrared (IR) radiation range of the electromagnetic spectrum and 332
produce varied images at different temperatures. As BAT is a thermogenic organ, it can transfer heat 333
energy across the overlying skin via IR emission upon activation by stimuli such as cold. Infrared 334
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thermography (IRT) has been utilised for BAT imaging in animals. In studies of BAT in mice, IRT 335
images of histologically-proven brown fat depots have been reported to correlate well with 18
F-FDG 336
uptake [88]. For BAT imaging in humans via IRT, this has been conducted in both children and adults 337
[89, 90]. Until recently, only one group has successfully verified the equivalence of IRT against 18
F-338
FDG PET/CT for BAT imaging in humans [91]. The highest increase in skin temperature with BAT 339
activation was found to be the supraclavicular area which corresponds to the largest BAT depot in 340
human adults. Following cold exposure, supraclavicular skin temperature declined much less than the 341
mediastinum area [92] while an increase in local temperature within the supraclavicular region has 342
been observed under both baseline and cold stimulated conditions despite the presence of an age-343
related decline in BAT heat output [89]. The temperature difference between supraclavicular area 344
and chest is consistently greater during cooling in BAT-positive subjects but not in BAT-negative 345
subjects as verified by PET/CT scan [91] (Figure 5). As examined by PET/CT, individuals with active 346
BAT compared to those without active BAT showed to have significantly higher local skin 347
temperatures at the supraclavicular region under thermoneutral condition. However, supraclavicular 348
subcutaneous adipose tissue thickness influences supraclavicular skin temperature, a factor that 349
reduces the sensitivity of IRT for BAT detection under thermoneutral conditions [93]. 350
One of the limitations of IRT is that it can only detect BAT in the superficial tissue, particularly over the 351
supraclavicular area. The thermogenicity of BAT located in deeper areas may be underestimated by 352
IRT. Therefore, the study of BAT activity in humans by IRT is limited to superficial BAT depots. 353
Nevertheless, it is notable that the supraclavicular and cervical regions possess the majority of BAT 354
depots in the body by far, which indicates that IRT of such superficial sites alone should account for 355
most of the heat power output by BAT. Overall, the extant literature supports the feasibility of IRT as a 356
promising novel non-invasive method in BAT detection/monitoring in adult humans. 357
358
Near-Infrared Time-Resolved Spectroscopy (NIRTRS) 359
Near-infrared spectroscopy (NIRS) was initiated in 1977 by Jobsis as a simple, non-invasive method 360
for measuring the presence of oxygen in muscle and other tissues in vivo [94]. Near-infrared time-361
resolved spectroscopy (NIRTRS) is a method developed to quantify optical properties such as 362
absorption (μa) and reduced scattering coefficients (μs), and total hemoglobin concentration [total-Hb] 363
which are respective indices of tissue vasculature and mitochondria content [95]. Since BAT has 364
abundant capillaries and mitochondria compared with WAT, this makes NIRTRS possible for 365
assessing BAT density [96]. Nirengi et al [97] compared the NIRTRS parameters (total hemoglobin 366
and reduced scattering coefficient) at 27ºC after 2h cold exposure at 19 ºC in the supraclavicular 367
region with 18
F-FDG-PET/CT-derived parameters (mean standardized uptake values) and found a 368
significant association between NIRTRS and 18
F-FDG PET/CT parameters. Moreover, there was no 369
difference between the NIRTRS parameters at 27ºC and during the 2-h cold exposure at 19 ºC in the 370
supraclavicular region which means NIRTRS may be capable of assessing BAT at room temperature 371
[97] (Figure 6). When subjects are exposed to thermogenic capsinoids ingested orally for 8 weeks, 372
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NIRTRS was able to detect an increase in BAT density during the 8-week treatment and a decrease 373
8-week follow-up period which means NIRTRS can be used for quantitative assessment of BAT in 374
longitudinal intervention studies in humans where 18
F-FDG PET/CT is difficult to use [98]. NIRTRS is 375
probably optimal for BAT evaluation only in supraclavicular region because other regions are greatly 376
influenced by hemoglobin and myoglobin concentrations in the muscle. However, NIRTRS method is 377
non-invasive, simple, and inexpensive and therefore is useful for detecting human BAT in the 378
supraclavicular region in normal and long term intervention studies with high sensitivity, specificity, 379
and accuracy [98]. It is also possible to combine NIRS with IRT to image BAT. 380
381
Ultrasound imaging (US) 382
Contrast-enhanced ultrasound (US) is a non-invasive method which can estimate blood flow to a 383
tissue by visualizing and quantifying intravenously infused microbubbles [99]. Contrast-enhanced US 384
has been established in cardiology without using ionising radiation and validated in the estimation of 385
myocardial blood flow in humans [100]. Continuous real-time imaging performed using contrast-386
enhanced US has been shown to reliably detect microvascular blood volume changes in skeletal 387
muscle and subcutaneous adipose tissue in humans [101, 102] . The blood flow in human 388
subcutaneous abdominal adipose tissue increases in the postprandial state as well as during and 389
after exercise probably related to lipid mobilization or deposition of lipids in the tissue, [102, 103], 390
since BAT is a highly vascularized tissue and BAT activation is associated with increased blood flow 391
and perfusion rate in humans [33, 56]. Hence, contrast-enhanced US may be a useful method to 392
evaluate the activation of BAT in humans. The presence of blood flow area imaged by contrast-393
enhanced ultrasound co-localized with BAT, as detected by 18
F-FDG PET/CT [104] (Figure 7). 394
Contrast-enhanced US as a non-invasive, nonionizing imaging feasibility may be a useful technique in 395
the assessment of BAT and BAT-targeted therapies by estimating BAT blood flow. However, it should 396
be noted that the measurements of BAT volume will be not reliable when subject’s BAT 397
vascularization and blood flow are significantly impaired, a factor limiting its accuracy in obese or 398
diabetic humans. 399
400
Conclusions 401
Apart from adipose tissue biopsy, several non-invasive imaging methods including PET/CT, MRI, IRT, 402
NIRTRS and contrast-enhanced US can be used to assess BAT. Although a number of recent 403
imaging advances have been made, it is clear that each technique has limitations and none is 404
superior in all aspects of evaluating BAT comprehensively (Table). Tissue biopsy is the only way to 405
accurately distinguish classical BAT from beige/brite BAT. Identified differences between brown and 406
beige/brite adipocytes currently reside at the cellular and genetic levels. While PET/CT has been the 407
most widely used imaging modality to study BAT activity and prevalence, it will eventually be 408
superseded by other precise imaging modalities lower in risks and costs. SPECT-CT utilizes tracers to 409
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12
detect BAT density and mitochondrial activity. However, just as for PET/CT, this method is also 410
limited by high costs, ionizing radiation and only metabolically active BAT detection. 411
MRI is a powerful and comprehensive imaging tool for BAT quantification. Perfusion techniques can 412
augment its capability to detect BAT metabolic activity through changes in oxygen consumption and 413
blood flow after BAT activation. Hence, MRI has the potential ability to detect both active and inactive 414
BAT without using ionizing radiation. MRI is likely to play a paramount role in BAT research 415
particularly if its costs can subsequently be reduced. Continued development and validation of MRI to 416
study BAT function are needed. 417
IRT, NIRTRS and contrast-enhanced US are also imaging modalities that do not employ ionizing 418
radiation. IRT detects BAT through skin temperature and heat emission overlying BAT in humans 419
while NIRTRS measures BAT density. However, their utility is restricted mainly to BAT localized to the 420
supraclavicular region. Contrast-enhanced US is based on detection of blood flow as a proxy of BAT 421
function. However, these three methods for BAT research require further validation. 422
In humans, the heterogenous appearance of beige adipocytes presents a challenge in assessing BAT 423
volume and mass. Continued refinement of presently available methods will escalate research that 424
ultimately increase our understanding of BAT metabolic regulation. 425
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Figure 1. Summary of the known environmental factors (eg. cold, nutraceuticals) and endogenous factors (eg. endocrine hormones) that activate brown and/or beige adipocyte activity and induce WAT browning. TRP: transient receptor potential; PUFA: polyunsaturated fatty acids; NE: norepinephrine; PPAR: Peroxisome Proliferator Activated Receptor subtype gamma; BMP: bone morphogenetic protein; SNS: sympathetic nervous system; FGF21: fibroblast growth factor subtype 21; ANP: atrial natriuretic peptide; BNP7: brain natriuretic peptide subtype 7; NPY: Neuropeptide Y; AT2R: Angiotensin II Type 2 receptor
Brown/Beige (‘Brite’) adipocyte
Capsaicin Capsinoids Omega-3 PUFA Ginger Menthol
Brain
SNS
TRP
NE
Bile acids FGF21 Irisin Thyroid hormones
PPAR agonists BMP7 ANP/BNP NPYApelin AT2R agonists
Energy expenditure
Counteracts against obesity, diabetes and related metabolic disorders
Cold exposure
Figure
A B
C D
Figure 2. 18F-FDG PET images from a healthy 31 years old female (A) and 23 years old male (B) subject under normal temperature and after wearing cooling vest for 1.5 hours (C and D, respectively). Increased FDG uptake was seen in the supraclavicular and paravertebral regions in the female subject.
Figure 3. Brown adipose tissue visualized with 123I-MIBG SPECT/CT (C and D) and 18F-FDG PET/CT (A and B). 18F-FDG and 123I-MIBG uptake on corresponding transversal PET and SPECT images is suggestive of BAT and is superimposed on adipose tissue on correlated transversal CT images. (Reprinted with permission from reference 66.)
Figure 4. fMRI detection of BAT activity on cold challenge (13°C–16°C). Degree of BOLD signal changes (red–yellow map) is superimposed on anatomic images. On cold stimulation, significant BOLD signal increases were found in regions identified as having BAT for subjects 1–3 (such as areas indicated by green circles). (Reprinted with permission from reference 76.)
A B C
D E F
Figure 5. Infrared thermograms of a 31-year old female confirmed as BAT-positive by 18F-FDG PET before (A), 1 hour post-cooling
vest (B) and 2 hours post-cooling vest (C) and a 23-year old male confirmed as BAT-negative by 18F-FDG PET before (D), 1 hour
post-cooling vest (E) and 2 hours post-cooling vest showing higher temperature in the supraclavicular fossa in the BAT-positive (31-
year old female) than the BAT-negative subject (23-year old male).
Figure 6. (A-C) The near-infrared time-resolved spectroscopy (NIRTRS) probe was placed in the supraclavicular region potentially containing brown adipose tissue (BAT) (corresponding to the black arrow heads in D and E panels), subclavicular region (corresponding to the white arrow heads in D and E panels), and deltoid muscle region (corresponding to the thin arrows) separated from BAT deposits. (D, E) Typical 18F-FDG PET/CT images. (Reprinted with permission from reference 97.)
A B
Figure 7. (A) Representative ultrasound image of BAT, located between the trapezius and sternocleidomastoid (SCM) muscles. The center of the adipose tissue ROI is approximately 1.5 cm below the skin surface. (B) Representative coronal 18F-FDG PET/CT image demonstrating 18F-FDG uptake in the region imaged by ultrasound. (Reprinted with permission from reference 104.)
Table
Main Imaging Modality Principle Advantage Disadvantage
18F-FDG PET/CT
Glucose metabolism with anatomic overlay
Widely used, extensive studies in clinical experience, showing BAT activation, excellent anatomic localization (CT spatial resolution: 0.5~1 mm), short acquisition time of 1-4 min.
Significant amount of ionizing radiation exposure, expensive (~$1500/scan), glucose is not the only energy source for BAT, limited sensitivity, moderate PET spatial resolution (6-10 mm).
18F-FDG PET/MR
Glucose metabolism with anatomic overlay
Lower amount of ionizing radiation than PET/CT, excellent anatomic localization (PET spatial resolution: 0.2 mm), capable of showing inactive and activated BAT
Very expensive (~$2000 /scan), glucose is not the only energy source for BAT, moderate PET spatial resolution (6-10 mm) and acquisition time of 1-10 min depending on the sequences used.
SPECT/CT
Sympathetic stimulation and activation with anatomic overlay
Utilize tracers to detect BAT density and mitochondrial activity, strong correlation with
18F-FDG PET/CT ,
excellent anatomic localization (CT spatial resolution: 0.5~1 mm)
Expensive (~$1000/scan), ionizing radiation and only metabolically active BAT detection, poor SPECT spatial resolution (7-15 mm) and acquisition time of 4-8 min.
MRI Fat water fraction
No ionizing radiation , detect inactivated BAT (fat fraction), able to detect activated BAT in functional BOLD-fMRI, widely available technique, excellent MR resolution (0.2 mm) and acquisition time of 1-10 min depending on the sequences used.
Noise sensitive, still quite costly (~$600/hour), limited specificity
IRT Skin temperature difference
No ionizing radiation, much lower cost , convenient, readily repeatable, short acquisition time of 1 s
Limited to superficially BAT depots, particularly over the supraclavicular area; uncertainty of skin temperature change arising from blood flow or thermogenic response in activated BAT, moderate spatial resolution (5 mm)
NIRS Oxygen content Non-invasive, simple, and inexpensive, short acquisition time of 1 ms
Limited to supraclavicular region, poor spatial resolution (10 mm)
Contrast-enhanced US Blood flow and perfusion
No ionizing radiation, lower cost, dynamic imaging possible, excellent MR resolution (0.1-1 mm), short acquisition time of 1 min
May not be reliable in some patients, difficult in tracing small clusters of BAT especially in humans, operator dependence
Table
