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1.  The Relationship between Brown Adipose Tissue Activity and Neoplastic Status: an 18F-FDG PET/CT Study in the Tropics 
Brown adipose tissue (BAT) has thermogenic potential. For its activation, cold exposure is considered a critical factor though other determinants have also been reported. The purpose of this study was to assess the relationship between neoplastic status and BAT activity by 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in people living in the tropics, where the influence of outdoor temperature was low.
18F-FDG PET/CT scans were reviewed and the total metabolic activity (TMA) of identified activated BAT quantified. The distribution and TMA of activated BAT were compared between patients with and without a cancer history. The neoplastic status of patients was scored according to their cancer history and 18F-FDG PET/CT findings. We evaluated the relationships between the TMA of BAT and neoplastic status along with other factors: age, body mass index, fasting blood sugar, gender, and outdoor temperature.
Thirty of 1740 patients had activated BAT. Those with a cancer history had wider BAT distribution (p = 0.043) and a higher TMA (p = 0.028) than those without. A higher neoplastic status score was associated with a higher average TMA. Multivariate analyses showed that neoplastic status was the only factor significantly associated with the TMA of activated BAT (p = 0.016).
Neoplastic status is a critical determinant of BAT activity in patients living in the tropics. More active neoplastic status was associated with more vigorous TMA of BAT.
PMCID: PMC3267802  PMID: 22182284
Neoplastic status; BAT; 18F-FDG PET
2.  Prevalence, Mass, and Glucose-Uptake Activity of 18F-FDG-Detected Brown Adipose Tissue in Humans Living in a Temperate Zone of Italy 
PLoS ONE  2013;8(5):e63391.
The 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area.
Methods and Findings
We retrospectively analyzed 6454 patients who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found 18F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with 18F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected.
This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of 18F-FDG-detected BAT.
PMCID: PMC3648481  PMID: 23667608
3.  The Prevalence and Characteristics of Brown Adipose Tissue in an 18F-FDG PET Study of Koreans 
The object of this study was to evaluate the prevalence and characteristics of brown adipose tissue (BAT) in Korean subjects using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET).
Six thousand and five consecutive 18F-FDG PET/CT scans of 5,115 patients (3,007 females and 2,108 males, mean age 53.5 years) were retrospectively reviewed. We characterized the nature of BAT, such as its location, and we assessed the influence of sex, age, body mass index (BMI), and temperature on BAT.
The prevalence of BAT in Koreans in a single 18F-FDG PET/CT scan in average conditions was 1.07%. The BAT detection rate was higher in females than males (1.32% vs 0.73%), and also with younger age (7.94% vs 0.73%), lower BMI (BMI with BAT, 21.1 vs BMI without BAT, 23.15) and cold outdoor temperature (1.65% vs 0.49%). The most frequent location of BAT was the supraclavicular area (left, 0.91%; right, 0.88%) and ventral neck area (left, 0.62%; right, 0.63%).
The characteristics of BAT in Koreans are not different from those described for Caucasians. However, the low prevalence of BAT in our study might be related to some scan condition like ambient temperature, but further study is needed.
PMCID: PMC4042938  PMID: 24899951
Brown adipose tissue; FDG; PET; Korean
4.  Assessment of Oxidative Metabolism in Brown Fat Using PET Imaging 
Objective: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, positron emission tomography (PET) imaging using the glucose analog 18F-deoxy-d-glucose (FDG) has shown unequivocally the existence of functional BAT in humans, suggesting that most humans have some functional BAT. The objective of this study was to determine, using dynamic oxygen-15 (15O) PET imaging, to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and FDG tracer uptake. Methods: Fourteen adult normal subjects (9F/5M, 30 ± 7 years) underwent triple oxygen scans (H215O, C15O, 15O2) as well as indirect calorimetric measurements at both rest and following exposure to mild cold (16°C). Subjects were divided into two groups (BAT+ and BAT−) based on the presence or absence of FDG tracer uptake (SUV > 2) in cervical–supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) was calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue (WAT). The metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to daily energy expenditure (DEE). Results: The median mass of activated BAT in the BAT+ group (5F, age 31 ± 8) was 52.4 g (range 14–68 g) and was 1.7 g (range 0–6.3 g) in the BAT − group (5M/4F, age 29 ± 6). Corresponding SUV values were significantly higher in the BAT+ as compared to the BAT− group (7.4 ± 3.7 vs. 1.9 ± 0.9; p = 0.03). Blood flow values in BAT were significantly higher in the BAT+ group as compared to the BAT− group (13.1 ± 4.4 vs. 5.7 ± 1.1 ml/100 g/min, p = 0.03), but were similar in WAT (4.1 ± 1.6 vs. 4.2 ± 1.8 ml/100 g/min) and muscle (3.7 ± 0.8 vs. 3.3 ± 1.2 ml/100 g/min). Moreover, OEF in BAT was similar in the two groups (0.56 ± 0.18 in BAT+ vs. 0.46 ± 0.19 in BAT−, p = 0.39). Calculated MRO2 values in BAT increased from 0.95 ± 0.74 to 1.62 ± 0.82 ml/100 g/min in the BAT+ group and were significantly higher than those determined in the BAT− group (0.43 ± 0.27 vs. 0.56 ± 0.24, p = 0.67). The DEE associated with BAT oxidative metabolism was highly variable in the BAT+ group, with an average of 5.5 ± 6.4 kcal/day (range 0.57–15.3 kcal/day). Conclusion: BAT thermogenesis in humans accounts for less than 20 kcal/day during moderate cold stress, even in subjects with relatively large BAT depots. Furthermore, due to the large differences in blood flow and glucose metabolic rates in BAT between humans and rodents, the application of rodent data to humans is problematic and needs careful evaluation.
PMCID: PMC3355936  PMID: 22649408
brown fat thermogenesis; oxidative metabolism; 15O PET imaging
5.  15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat 
Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog 18F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and 18F-FDG tracer uptake.
Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H215O, C15O, and 15O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of 18F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical–supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE.
The mass of activated BAT was 59.1 ± 17.5 g (range, 32–85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0–9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40 ± 0.28 vs. 0.51 ± 0.23, P = 0.67). The increase in DEE associated with BAT oxidative metabolism was highly variable in the high-BAT group, with an average of 3.2 ± 2.4 kcal/d (range, 1.9–4.6 kcal/d) at rest, and increased to 6.3 ± 3.5 kcal/d (range, 4.0–9.9 kcal/d) during exposure to mild cold. Although BAT accounted for only a small fraction of the cold-induced increase in DEE, such increases were not observed in subjects lacking BAT.
Mild cold-induced thermogenesis in BAT accounts for 15–25 kcal/d in subjects with relatively large BAT depots. Thus, although the presence of active BAT is correlated with cold-induced energy expenditure, direct measurement of MRO2 indicates that BAT is a minor source of thermogenesis in humans.
PMCID: PMC3883579  PMID: 23362317
brown fat thermogenesis; BAT oxidative metabolism; 15O PET imaging
6.  Impact of Age on the Relationships of Brown Adipose Tissue With Sex and Adiposity in Humans 
Diabetes  2010;59(7):1789-1793.
Brown adipose tissue (BAT) regulates energy homeostasis and fat mass in mammals and newborns and, most likely, in adult humans. Because BAT activity and BAT mass decline with age in humans, the impact of BAT on adiposity may decrease with aging. In the present study we addressed this hypothesis and further investigated the effect of age on the sex differences in BAT activity and BAT mass.
Data from 260 subjects (98 with BAT and 162 study date–matched control subjects) who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) under thermoneutral conditions were analyzed. BAT activity and BAT mass were determined in the upper body.
BAT activity and BAT mass were higher in female (1.59 ± 0.10 and 32 ± 5 g vs. 1.02 ± 0.10 and 18 ± 4 g, both P ≤ 0.0006) than in male subjects. In multivariate analyses, sex (P < 0.0001), age (P < 0.0001), and BMI (P = 0.0018) were associated independently with BAT activity. Interestingly, only in male subjects was there an interaction between BMI and age in determining BAT activity (P = 0.008) and BAT mass (P = 0.0002); BMI decreased with increasing BAT activity and BAT mass in the lowest age tertile (Spearman rank correlation coefficient rs = −0.38, P = 0.015 and rs = −0.37, P = 0.017, respectively), not in the higher age tertiles. Furthermore, BAT activity and mass differed between female and male subjects only in the upper two age tertiles (all P ≤ 0.09).
Our data corroborate that, in general, BAT activity and BAT mass are elevated in female subjects and in younger people. Importantly, we provide novel evidence that the impact of BAT activity and BAT mass on adiposity appears to decline with aging only in male subjects. Furthermore, while BAT activity and BAT mass only moderately decline with increasing age in female subjects, a much stronger effect is found in male subjects.
PMCID: PMC2889780  PMID: 20357363
7.  Brown Adipose Tissue in Morbidly Obese Subjects 
PLoS ONE  2011;6(2):e17247.
Cold-stimulated adaptive thermogenesis in brown adipose tissue (BAT) to increase energy expenditure is suggested as a possible therapeutic target for the treatment of obesity. We have recently shown high prevalence of BAT in adult humans, which was inversely related to body mass index (BMI) and body fat percentage (BF%), suggesting that obesity is associated with lower BAT activity. Here, we examined BAT activity in morbidly obese subjects and its role in cold-induced thermogenesis (CIT) after applying a personalized cooling protocol. We hypothesize that morbidly obese subjects show reduced BAT activity upon cold exposure.
Methods and Findings
After applying a personalized cooling protocol for maximal non-shivering conditions, BAT activity was determined using positron-emission tomography and computed tomography (PET-CT). Cold-induced BAT activity was detected in three out of 15 morbidly obese subjects. Combined with results from lean to morbidly obese subjects (n = 39) from previous study, the collective data show a highly significant correlation between BAT activity and body composition (P<0.001), respectively explaining 64% and 60% of the variance in BMI (r = 0.8; P<0.001) and BF% (r = 0.75; P<0.001). Obese individuals demonstrate a blunted CIT combined with low BAT activity. Only in BAT-positive subjects (n = 26) mean energy expenditure was increased significantly upon cold exposure (51.5±6.7 J/s versus 44.0±5.1 J/s, P = 0.001), and the increase was significantly higher compared to BAT-negative subjects (+15.5±8.9% versus +3.6±8.9%, P = 0.001), indicating a role for BAT in CIT in humans.
This study shows that in an extremely large range of body compositions, BAT activity is highly correlated with BMI and BF%. BAT-positive subjects showed higher CIT, indicating that BAT is also in humans involved in adaptive thermogenesis. Increasing BAT activity could be a therapeutic target in (morbid) obesity.
PMCID: PMC3044745  PMID: 21390318
8.  Infrared thermography in the detection of brown adipose tissue in humans 
Physiological Reports  2014;2(11):e12167.
PET‐CT using 18F‐FDG is employed for detecting brown adipose tissue (BAT) in humans. Alternative methods are needed because of the radiation and cost of PET‐CT imaging. The aim was to evaluate the accuracy of infrared thermography (IRT) in detecting human BAT benchmarked to PET‐CT imaging. Seventeen individuals underwent a total of 29 PET‐CT scans, 12 of whom were studied twice, after 2 h of cold stimulation at 19°C, in parallel with measurement of skin temperatures overlying the supraclavicular (SCV) fossa and the lateral upper chest (control), before and after cold stimulation. Of the 29 scans, 20 were BAT positive after cold stimulation. The mean left SCV temperature tended to be higher in the BAT‐positive group before and during cooling. It was significantly higher (P =0.04) than the temperature of the control area, which fell significantly during cooling in the BAT‐positive (−1.2 ± 0.3°C, P =0.002) but not in the negative (−0.2 ± 0.4°C) group. The temperature difference (Δtemp) between left SCV and chest increased during cooling in the BAT‐positive (1.2 ± 0.2 to 2.0 ± 0.3°C, P <0.002) but not in the negative group (0.6 ± 0.1 to 0.7 ± 0.1°C). A Δtemp of 0.9°C conferred a positive predictive value of 85% for SCV BAT, superior to that of SCV temperature. The findings were similar on the right. In conclusion, the Δtemp is significantly and consistently greater in BAT‐positive subjects. The Δtemp quantified by IRT after 2‐h cooling shows promise as a noninvasive convenient technique for studying SCV BAT function.
Using infrared thermography (IRT), we observed the skin temperature of the supraclavicular fossa (SCV) where brown adipose tissue (BAT) is present, to be higher than that of a control BAT‐negative chest area. This temperature difference was greater in subjects with BAT and conferred a positive predictive value of 85% for BAT benchmarked to PET/CT imaging. IRT shows promise as a tool for detecting BAT function in humans.
PMCID: PMC4255799  PMID: 25413316
Brown adipose tissue; human; infrared thermography; thermogenesis
9.  Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation 
EJNMMI Research  2011;1:30.
Brown adipose tissue [BAT] metabolism in vivo is vital for the development of novel strategies in combating obesity and diabetes. Currently, BAT is activated at low temperatures and measured using 2-deoxy-2-18F-fluoro-D-glucose [18F-FDG] positron-emission tomography [PET]. We report the use of β3-adrenergic receptor-mediated activation of BAT at ambient temperatures using (R, R)-5-[2-[2,3-(3-chlorphenyl)-2-hydroxyethyl-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disodium salt [CL316,243] (a selective β3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT].
Control and CL316,243-treated (2 mg/kg) male Sprague-Dawley rats were administered with 18F-FDG for PET/CT studies and were compared to animals at cold temperatures. Receptor-blocking experiments were carried out using propranolol (5 mg/kg). Dose effects of CL316,243 were studied by injecting 0.1 to 1 mg/kg 30 min prior to 18F-FDG administration. Imaging results were confirmed by autoradiography, and histology was done to confirm BAT activation.
CL316,243-activated interscapular BAT [IBAT], cervical, periaortic, and intercostal BATs were clearly visualized by PET. 18F-FDG uptake of IBAT was increased 12-fold by CL316,243 vs. 1.1-fold by cold exposure when compared to controls. 18F-FDG uptake of the CL-activated IBAT was reduced by 96.0% using intraperitoneal administration of propranolol. Average 18F-FDG uptake of IBAT increased 3.6-, 3.5-, and 7.6-fold by doses of 0.1, 0.5, and 1 mg/kg CL, respectively. Ex vivo 18F-FDG autoradiography and histology of transverse sections of IBAT confirmed intense uptake in the CL-activated group and activated IBAT visualized by PET.
Our study indicated that BAT metabolic activity could be evaluated by 18F-FDG PET using CL316,243 at ambient temperature in the rodent model. This provides a feasible and reliable method to study BAT metabolism.
PMCID: PMC3250993  PMID: 22214183
BAT; CL316,243; β3-adrenoceptor; 18F-FDG; obesity
10.  Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity 
PLoS ONE  2011;6(6):e21006.
Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity.
Methodology/Principal Findings
We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities.
Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.
PMCID: PMC3118816  PMID: 21701596
11.  Evaluation of 18F-FDG Uptake Pattern in Brown Adipose Tissue Over Extended Time Period as Assessed by Multiple Time Point 18F-FDG-PET 
To study the 18F-FDG uptake pattern in brown adipose tissue (BAT) over an extended time period, by multiple-time-point fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. The primary objective for this kind of research was that it could form a basis and may have further implications for obesity research, metabolic diseases and for cachexia of both malignant and benign origin.
A total of 12 patients who had undergone routine FDG-PET for disease evaluation and had demonstrated prominent BAT uptake in their baseline scans were selected. The patients with the diagnosis of neuroendocrine tumors were excluded. Maximum standardized uptake values (SUVmax) were calculated in the BAT of the supraclavicular and paravertebral areas of either side, and were analyzed separately to examine their behavior individually. Time activity curves (TACs) were generated for [A] BAT SUVmax values and [B] SUVmax ratio of BAT/lung (B/L SUVmax ratio) at various time points.
Ten out of the 12 patients were imaged at four time points, and two patients were imaged for two time points. Amongst a total of n = 30 sites, 23 were imaged at four time points and seven were imaged at two time points. Seventeen out of 30 area sites (56.67 %) demonstrated a peak value at 60 min and a falling trend of SUVmax afterwards; the remaining showed a peak uptake value between 85 and 300 min after the first scan (i.e. 145–360 min after injection), and falling values thereafter. With regard to the B/L SUVmax ratio, ten out of 30 sites (33.33 %) demonstrated peak uptake at 60 min, and the remaining showed a rise, with peak uptake at times between 85 and 300 min after the first scan (i.e. 145–360 min after injection) and falling values thereafter. No additional area of BAT uptake was observed over the extended time period in this study.
Wide variability was observed in the BAT FDG uptake over an extended period of time. Nearly half of the sites demonstrated an increase in FDG uptake until 360 min (i.e. 6 h) after injection, while the remaining half showed peak uptake at 1 h and subsequent fall of uptake. In the future, it will be worthwhile to study whether there exists any difference in time course of FDG uptake in brown fat between patients with cancer and those scanned for benign etiologies, or between obese and non-obese individuals.
PMCID: PMC4041975  PMID: 24900088
FDG-PET; Brown adipose tissue; Multiple time point studies; Brown fat
12.  Control and Physiological Determinants of Sympathetically Mediated Brown Adipose Tissue Thermogenesis 
Brown adipose tissue (BAT) represents a remarkable heat-producing tissue. The thermogenic potential of BAT is conferred by uncoupling protein 1, a protein found uniquely in brown adipocytes. BAT activity and capacity is controlled by the sympathetic nervous system (SNS), which densely innervates brown fat depots. SNS-mediated BAT thermogenesis is essentially governed by hypothalamic and brainstem neurons. BAT activity is also modulated by brain energy balance pathways including the very significant brain melanocortin system, suggesting a genuine involvement of SNS-mediated BAT thermogenesis in energy homeostasis. The use of positron emission tomography/computed tomography scanning has revealed the presence of well-defined BAT depots in the cervical, clavicular, and paraspinal areas in adult humans. The prevalence of these depots is higher in subjects exposed to low temperature and is also higher in women compared to men. Moreover, the prevalence of BAT decreases with age and body fat mass, suggesting that BAT could be involved in energy balance regulation and obesity in humans. This short review summarizes recent progress made in our understanding of the control of SNS-mediated BAT thermogenesis and of the determinants of BAT prevalence or detection in humans.
PMCID: PMC3356074  PMID: 22654862
energy balance; energy expenditure; melanocortin system; cold exposure; age; sex; environmental temperature; positron emission tomography
13.  Seasonal Effects of UCP1 Gene Polymorphism on Visceral Fat Accumulation in Japanese Adults 
PLoS ONE  2013;8(9):e74720.
Uncoupling protein 1 (UCP1) and β3 adrenergic receptor (ADRB3) genes play central roles in the thermogenesis of brown adipose tissue (BAT) in adult humans. However, the importance of single-nucleotide polymorphisms (SNPs) in both genes during the development of obesity is controversial. Although active BAT in adult humans is frequently observed in the winter season, the effects of sampling season have not been taken into consideration in previous association studies. Here, we tested the associations of UCP1 -3826A/G and ADRB3 Trp64Arg with body mass index (BMI) and visceral fat area (VFA) in 3013 Japanese adults sampled during different seasons. Association between SNPs and the obesity-related traits were assessed using multiple linear regression models, including sex, age, physical activity, and genotypes. Both SNPs did not show significant associations in the models based on the entire cohort. However, in subsets comprising individuals mainly sampled from winter to spring, UCP1 showed significant associations with VFA (P = 0.0098) and VFA adjusted for BMI (P = 0.0128). Moreover, the effects of UCP1 on VFA were strongly negatively correlated with outdoor temperature (P = 0.00011), but not with night length (P = 0.039). ADRB3 did not show these associations, but an additive effect with UCP1 was observed for VFA adjusted for BMI (P = 0.0067). Subsets sampled in the hot season did not show significant associations for both SNPs. The season-specific effects of UCP1 on VFA were consistent with a previous finding that active BAT was more frequently found in winter than in summer, and supported the importance of cold stress in BAT activation and the significance of BAT in the development of obesity in adult humans.
PMCID: PMC3783463  PMID: 24086366
14.  In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging 
PLoS ONE  2013;8(4):e62007.
Brown adipose tissue (BAT), a specialized tissue for thermogenesis, plays important roles for metabolism and energy expenditure. Recent studies validated BAT’s presence in human adults, making it an important re-emerging target for various pathologies. During this validation, PET images with 18F-FDG showed significant uptake of 18F-FDG by BAT under certain conditions. Here, we demonstrated that Cerenkov luminescence imaging (CLI) using 18F-FDG could be utilized for in vivo optical imaging of BAT in mice.
Mice were injected with 18F-FDG and imaged 60 minutes later with open filter and 2 minute acquisition. In vivo activation of BAT was performed by norepinephrine and cold treatment under isoflurane or ketamine anesthesia. Spectral unmixing and 3D imaging reconstruction were conducted with multiple-filter CLI images.
1) It was feasible to use CLI with 18F-FDG to image interscapular BAT in mice, with the majority of the signal (>85%) at the interscapular site originating from BAT; 2) The method was reliable because excellent correlations between in vivo CLI, ex vivo CLI, and ex vivo radioactivity were observed; 3) CLI could be used for monitoring BAT activation under different conditions; 4) CLI signals from the group under short-term isoflurane anesthesia were significantly higher than that from the group under long-term anesthesia; 5) The CLI spectrum of 18F-FDG with a peak at 640 nm in BAT after spectral unmixing reflected the actual context of BAT; 6) Finally 3D reconstruction images showed excellent correlation between the source of the light signal and the location and physical shape of BAT.
CLI with 18F-FDG is a feasible and reliable method for imaging BAT in mice. Compared to PET imaging, CLI is significantly cheaper, faster for 2D planar imaging and easier to use. We believe that this method could be used as an important tool for researchers investigating BAT.
PMCID: PMC3634850  PMID: 23637947
15.  Positive effects of brown adipose tissue on femoral bone structure 
Bone  2013;58:10.1016/j.bone.2013.10.007.
Recent studies suggest a link between brown adipose tissue (BAT) and bone. The purpose of our study was to investigate the effects of BAT on femoral bone structure.
Materials and Methods
We studied 105 patients (19 m, 86 f, mean age 45.5±16.1 y) who underwent F18-FDG positron emission tomography/computed tomography (PET/CT) for benign etiologies (n=20) or follow-up of successfully treated malignancies (n=85); mean time between PET/CT and last form of treatment was 14.8±18.0 months. BAT volume by PET/CT; femoral bone structure by CT (total femoral cross-sectional area (CSA), cortical CSA); thigh muscle CSA and thigh subcutaneous fat CSA by CT were assessed.
There were positive correlations between BAT volume and total femoral CSA and cortical CSA, independent of age, BMI and history of malignancy (P<0.05). BAT volume correlated positively with thigh muscle CSA and thigh fat CSA (p<0.05). When total femoral CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables in a forward stepwise regression model, BAT volume was the only predictor of total femoral CSA. When femoral cortical CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables, BAT volume was the only predictor of femoral cortical CSA.
BAT volume is a positive predictor of femoral bone structure and correlates positively with thigh muscle and subcutaneous fat, possibly mediated by muscle. These results provide further evidence of a positive effect of BAT on bone.
PMCID: PMC3855336  PMID: 24140784
brown adipose tissue (BAT); bone; structure; muscle; fat
16.  Targeting Presynaptic Norepinephrine Transporter in Brown Adipose Tissue: A Novel Imaging Approach and Potential Treatment for Diabetes and Obesity 
Synapse (New York, N.Y.)  2012;67(2):10.1002/syn.21617.
Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for 18F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous 18F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before 18F-FDG administration. To confirm the β-adrenergic effects, propranolol (β-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In 18F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the 18F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average 18F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of 18F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of β3-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates β3-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by 18F-FDG PET/CT.
PMCID: PMC3808851  PMID: 23080264
atomoxetine; blood glucose; 18F-FDG PET; Brown fat
17.  18F-Fluorobenzyl Triphenyl Phosphonium: A Noninvasive Sensor of Brown Adipose Tissue Thermogenesis 
Recent studies have proposed activation of brown adipose tissue (BAT) thermogenesis as a new strategy to combat obesity. Currently, there is no effective noninvasive imaging agent to directly detect unstimulated BAT and quantify the core mechanism of mitochondrial thermogenesis. We investigated an approach to detect BAT depots and monitor thermogenesis using the mitochondria-targeting voltage sensor radiolabeled fluorobenzyltriphenyl phosphonium (FBnTP).
18F-FBnTP, 14C-FBnTP, 18F-FDG, and 99mTc-sestamibi uptake in BAT at room temperature (n = 8) and cold-treated (n = 8) Lewis rats was assayed. The effect of the cold condition on 18F-FBnTP retention in BAT was assessed in 8 treated and 16 control rats. The effect of the noradrenergic inhibitor propranolol on 14C-FBnTP response to cold stimulation was investigated in an additional 8 treated and 8 control mice.
At room temperature, 18F-FBnTP accumulated in BAT to an extent similar to that in the heart, second only to the kidney and twice as much as 99mTc-sestamibi. Prior exposure to cold (4 °C) for 4 h resulted in an 82% decrease of 14C-FBnTP uptake and an 813% increase of 18F-FDG uptake in BAT. 99mTc-sestamibi uptake was not affected by cold. Administration of 18F-FBnTP at room temperature 60 min before 120 and 240 min of exposure to cold resulted in marked washout of the tracer from BAT. Propranolol significantly diminished the effect of cold on 14C-FBnTP and 18F-FDG uptake into BAT.
The intense uptake of 18F-FBnTP into BAT at room temperature and the response to cold stimulation suggest the unique potential advantage of 18F-FBnTP not only in detecting unstimulated BAT at high contrast but also in quantifying the mitochondrial thermogenic activity. 18F-FBnTP PET may serve as a useful technique to assess BAT volume and function.
PMCID: PMC4332805  PMID: 21498536
PET; 18F-FBnTP; 18F-FDG; brown adipose tissue; thermogenesis
18.  Intravenous administration of diazepam significantly reduces brown fat activity on 18F-FDG PET/CT 
Brown adipose tissue (BAT) activity on 18F-fluorodeoxyglucose (FDG) PET/CT can introduce an undesirable element of complexity when attempting to discern physiologic activity from more ominous entities. Recent studies have demonstrated several methods to reduce BAT FDG uptake. Benzodiazepines, however, have yet to been proven effective against BAT.
Twenty-five patients with increased BAT FDG uptake were selected retrospectively from our PET/CT database between November 2004 and January 2011. These patients had been asked to return on a different day for repeat scanning with 5mg of intravenous diazepam, administered ten minutes prior to FDG. Two patients underwent this procedure on a second occasion (for a follow-up scan at a later date), thus resulting in a total of twenty-seven scans from twenty five patients. FDG uptake in BAT was recorded using the maximum standardized uptake value (SUVmax).
The mean basal BAT SUVmax was 10.1 ± 4.6 compared to a mean SUVmax of 2.8 ± 3.3 post IV diazepam (p < 0.0001). Approximately 89% (24 of 27) of scans had no significant residual BAT activity. The three remaining scans had a reduction in SUVmax ranging from 23-64% following diazepam administration. No adverse effects were noted.
We observed a significant reduction in brown fat activity in para-spinal, cervical, mediastinal, para-adrenal, and supra- and infra-clavicular regions on PET/CT following premedication with intravenous diazepam. We feel that IV benzodiazepines should be considered a pharmacologic option for reducing BAT FDG uptake, which in turn, will aid in distinguishing physiologic metabolic activity from pathology.
PMCID: PMC3477718  PMID: 23133792
Brown adipose tissue; diazepam; 18F-FDG PET
19.  Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans 
Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.
PMCID: PMC3266793  PMID: 22269323
20.  The Role and Importance of Brown Adipose Tissue in Energy Homeostasis 
Current opinion in pediatrics  2010;22(4):478-484.
Purpose of review
Children and adults have two major types of adipocytes, which represent the predominant cells in white adipose tissue (WAT), which is involved in energy-storage, and brown adipose tissue (BAT) which is responsible for thermogenesis and energy expenditure. This review discusses BAT physiology and evaluates the recent discoveries regarding its development, identification, and function.
Recent findings
This past year multiple independent research teams using combined positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression have proven conclusively that adult humans have functional BAT. In parallel, basic studies defined BAT origins, its transcriptional regulation, and the role of hormones in BAT growth and activation. These methods have begun to be applied to children to understand pediatric BAT anatomy and physiology.
Adult humans have functional BAT, which plays a role in energy balance. BAT is more prevalent in children, suggesting an even greater physiological role than that seen in adults. Future studies will identify safe ways to quantify BAT mass and activity and which interventions might be used to increase BAT mass and/or thermogenesis to treat obesity.
PMCID: PMC3593062  PMID: 20489634
brown adipose tissue; energy balance; UCP-1; PET/CT
21.  Relevance of brown adipose tissue in infancy and adolescence 
Pediatric research  2012;73(1):3-9.
Brown adipose tissue (BAT) was thought to disappear after infancy. Recent studies finding BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggests that BAT is more prevalent in children than in adults, and that its activation during adolescence is associated to significantly less gains in weight and adiposity. Data also shows that pediatric patients with metabolically-active BAT on PET/CT examinations have significantly greater muscle volume than patients with no identifiable BAT. Both the activity and the amount of BAT increase during puberty. The magnitude of the increase is higher in boys when compared to girls, and closely related to gains in muscle volume. Hence, concurrent with the great gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between brown adipocytes, white adipocytes, and myocites. In this review, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children.
PMCID: PMC3614088  PMID: 23090604
22.  Supraclavicular Skin Temperature as a Measure of 18F-FDG Uptake by BAT in Human Subjects 
PLoS ONE  2014;9(6):e98822.
Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current ‘gold standard’ for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans.
BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations.
Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not.
Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects.
Trial Registration
NTR 2473
PMCID: PMC4055666  PMID: 24922545
23.  Brown Adipose Tissue and Seasonal Variation in Humans 
Diabetes  2009;58(11):2583-2587.
Brown adipose tissue (BAT) is present in adult humans where it may be important in the prevention of obesity, although the main factors regulating its abundance are not well established. BAT demonstrates seasonal variation relating to ambient temperature and photoperiod in mammals. The objective of our study was therefore to determine whether seasonal variation in BAT activity in humans was more closely related to the prevailing photoperiod or temperature.
We studied 3,614 consecutive patients who underwent positron emission tomography followed by computed tomography scans. The presence and location of BAT depots were documented and correlated with monthly changes in photoperiod and ambient temperature.
BAT activity was demonstrated in 167 (4.6%) scans. BAT was demonstrated in 52/724 scans (7.2%) in winter compared with 27/1,067 (2.5%) in summer months (P < 0.00001, χ2 test). Monthly changes in the occurrence of BAT were more closely related to differences in photoperiod (r2 = 0.876) rather than ambient temperature (r2 = 0.696). Individuals with serial scans also demonstrated strong seasonal variation in BAT activity (average standardized uptake value [SUVmax] 1.5 in July and 9.4 in January). BAT was also more common in female patients (female: n = 107, 7.2%; male: n = 60, 2.8%; P < 0.00001, χ2 test).
Our study demonstrates a very strong seasonal variation in the presence of BAT. This effect is more closely associated with photoperiod than ambient temperature, suggesting a previously undescribed mechanism for mediating BAT function in humans that could now potentially be recruited for the prevention or reversal of obesity.
PMCID: PMC2768171  PMID: 19696186
24.  An Automated Algorithm to Identify and Quantify Brown Adipose Tissue in Human 18F-FDG-PET/CT Scans 
Obesity (Silver Spring, Md.)  2013;21(8):1554-1560.
To develop an algorithm to identify and quantify BAT from PET/CT scans without radiologist interpretation.
Design and Methods
Cases (n = 17) were randomly selected from PET/CT scans with documented “brown fat” by the reviewing radiologist. Controls (n = 18) had no documented “brown fat” and were matched with cases for age (49.7 [31.0-63.0] vs. 52.4 [24.0-70.0] yrs), outdoor temperature at scan date (51.8 [38.9-77.0] vs. 54.9 [35.2-74.6] °F), sex (F/M: 15/2 cases; 16/2 controls) and BMI (28.2 [20.0-45.7] vs. 26.8 [21.4-37.1] kg/m2]). PET/CT scans and algorithm-generated images were read by the same radiologist blinded to scan identity. Regions examined included neck, mediastinum, supraclavicular fossae, axilla and paraspinal soft tissues. BAT was scored 0 for no BAT; 1 for faint uptake possibly compatible with BAT or unknown; and 2 for BAT positive.
Agreement between the algorithm and PET/CT scan readings was 85.7% across all regions. The algorithm had a low false negative (1.6%) and higher false positive rate (12.7%). The false positive rate was greater in mediastinum, axilla and neck regions.
The algorithm's low false negative rate combined with further refinement will yield a useful tool for efficient BAT identification in a rapidly growing field particularly as it applies to obesity.
PMCID: PMC3910095  PMID: 23408435
25.  Brown Adipose Tissue Can Be Activated or Inhibited within an Hour before 18F-FDG Injection: A Preliminary Study with MicroPET 
Brown adipose tissue (BAT) is emerging as a potential target for treating human obesity. It has been indicated that BAT is rich in innervations of sympathetic nerve control. Using 18F-FDG microPET imaging, this study aims at evaluating how factors related to sympathetic activation/inhibition changed BAT metabolism of mice. BAT 18F-FDG uptake were semiquantitatively evaluated in different groups of mice under temperature (cold or warm stimulus) or pharmacological interventions (norepinephrine, epinephrine, isoprenaline, or propranolol) and were compared with the corresponding controls. It was found that BAT activation can be stimulated by cold exposure (P = 1.96 × 10−4), norepinephrine (P = .002), or both (P = 2.19 × 10−6) within an hour before 18F-FDG injection and can also be alleviated by warming up (P = .001) or propranolol lavage (P = .027). This preliminary study indicated that BAT function could be evaluated by 18F-FDG PET imaging through short-term interventions, which paved the way for further investigation of the relationship between human obesity and BAT dysfunction.
PMCID: PMC3085214  PMID: 21541240

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