Human brown adipose tissue (BAT) can be activated to increase glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. Data on the functional ...and anatomic characteristics of BAT are limited, however. In 20 healthy young men 12 lean, mean body mass index (BMI) 23.2 ± 1.9 kg/m²; 8 obese, BMI 34.8 ± 3.3 kg/m² after 5 h of tolerable cold exposure, we measured BAT volume and activity by 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.1–71%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT—cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal—with 67 ± 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential.
In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been ...investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24 °C month 1 → 19 °C month 2 → 24 °C month 3 → 27 °C month 4) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits.
High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and ...systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.
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•Brown fat utilizes glucose as substrate fuel to produce heat in humans•Human brown fat exhibits a thermogenic circadian rhythm•Brown fat circadian rhythm is glucose responsive•Low brown fat abundance is associated with greater glycaemic fluctuations
Lee et al. reveal how glucose utilization by brown fat in humans is coupled with heat production in a circadian manner. Higher brown fat abundance correlates with lesser glycemia variability, suggesting that brown fat may help buffer glucose fluctuations and maintain whole-body glucose homeostasis over time.
Context:
The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations ...of both BAT activity and energy expenditure (EE).
Objective:
The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT).
Design:
This study was a single-blind, randomized crossover intervention.
Setting:
The study was conducted at the National Institutes of Health Clinical Center.
Study Participants:
Thirty-one healthy volunteers participated in the study.
Interventions:
The intervention included mild cold exposure.
Main Outcomes:
CIT and BAT activation were the main outcomes in this study.
Methods:
Overnight EE measurement by whole-room indirect calorimeter at 24°C or 19°C was followed by 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures.
Results:
Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24°C, exposure at 19°C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT.
Conclusions:
A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.
Positron emission tomography (PET) attenuation correction (AC) using computed tomography (CT) can be affected by respiratory motion: hi-speed CT captures 1 point of the respiratory cycle while PET ...emission data averages many cycles. We quantified the changes in apparent myocardial uptake due to this respiratory-induced CT attenuation mismatch.
Twenty-two patients undergoing fluorine-18 fluorodexyglucose (FDG) PET/CT received 3 sequential CT scans at normal resting end-inspiration (CT
INSPIR), ending expiration (CT
EXPIR), and at midvolume between end-expiration and end-inspiration (CT
MIDVOL). A pneumotachometer measured absolute changes in lung volume. Seven subjects also underwent a 3-minute transmission scan with a
68Ge rotating rod source (RRS). The PET emission data set was reconstructed up to 4 times using CT
EXPIR, CT
INSPIR, CT
MIDVOL, and RRS AC maps. Relative heart position and cardiac uptake was measured for each CT attenuation correction.
Respiratory motion produced marked changes in global and regional myocardial uptake. Changes were large in the lateral and anterior regions at the lung-soft tissue interface (up to 30% using CT
INSPIR compared to CT
EXPIR for AC) and smaller in the septal region (10% or less). Data corrected with CT
EXPIR agreed best with the RRS.
Respiratory effects can introduce large inhomogeneities in apparent myocardial uptake when CT is used for attenuation correction.
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Eligibility for somatostatin receptor (SSTR) radionuclide therapy uses the qualitative Krenning score based on
In-pentetreotide planar scintigraphy as was performed in the NETTER-1 trial. The purpose ...of this study was to determine the effect of using SSTR PET-based Krenning score in comparison to
In-pentetreotide.
This was a post hoc head-to-head comparison of
Ga-DOTATATE-based and
In-pentetreotide-based Krenning scores in 150 patients included in a prospective phase 2 study (NCT01967537). Patients were imaged using
Ga-DOTATATE PET/CT,
In-pentetreotide planar scintigraphy, and SPECT/CT within 1 wk. SSTR ligand uptake was graded using the Krenning score independently by 3 readers.
The detection rate of SSTR-expressing disease (Krenning scores 2-4) was 23%, 38%, and 72% with planar imaging, SPECT, and SSTR PET, respectively. The Krenning score was higher with SSTR PET (2.71 ± 1.74) than with planar imaging (0.75 ± 1.37;
< 0.001) or SPECT (1.23 ± 1.57;
< 0.001). In patients with a Krenning score of at least 3 on SSTR PET, the detection rate of planar imaging and SPECT was lower for lesions smaller than 2 cm than lesions 2 cm or larger: 15% and 24% versus 78% and 89%, respectively (
< 0.001). For lesions larger than 5 cm, Krenning scores between SSTR PET and
In-pentetreotide were nearly equivalent. Lesion size did not have an impact on SSTR PET Krenning scores. Interreader agreement was higher for SSTR PET than for planar imaging or SPECT (0.79 vs. 0.67 and 0.50, respectively).
SSTR PET results in higher Krenning scores than
In-pentetreotide, particularly when lesions measured 2 cm or less. Small lesion size resulted in low Krenning scores using
In-pentetreotide, but lesion size did not affect SSTR PET-based Krenning scores. The results of the NETTER-1 trial cannot be directly applied to patients with small lesions. Further study of peptide receptor radionuclide therapy in patients with small lesions negative on
In-pentetreotide imaging and positive on SSTR PET is warranted.
Background
Adrenocortical carcinoma (ACC) is a rare but lethal malignancy with few reliable prognostic markers. FDG-PET metabolic parameters have been shown to predict survival in several cancers. ...The objective was to determine if metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUV
max
) could serve as prognostic markers in patients with ACC.
Methods
A total of 30 patients with ACC prospectively underwent 18F-FDG PET/CT prior to treatment. Whole body MTV, TLG, and SUV
max
were measured by a semiautomatic method. A median cutoff was used to determine an association with overall survival (OS) from the time of 18F-FDG PET/CT by the Kaplan–Meier method.
Results
Patients with high whole body MTV (>87.0 mL),TLG (>229.4 SUV
lbm
*mL), or SUV
max
(>8.9 SUV) had a worse OS compared with those with low whole body MTV (median OS, 24 vs 45.1 months,
p
< .01), TLG (median OS, 24 vs 40.3 months,
p
< .005), or SUV
max
(median OS, 23.7 vs 35.5 months,
p
< .02). In patients who had operable disease (
n
= 23), high whole body MTV (>87.0 mL) and TLG (>229.4 SUV
lbm
*mL) had a worse OS compared with those with low whole body MTV (median OS, 25.1 vs 45.1 months,
p
< .05) and TLG (median OS, 25.1 vs 40.3 months,
p
< .05), but a high SUV
max
(>8.9 SUV) was not associated with worse OS (
p
= .11).
Conclusions
Patients with ACC and a high whole body MTV, TLG, and SUV
max
have a worse prognosis and OS. Measurement of whole body MTV and TLG may be helpful for guiding therapy for patients with ACC.
The aim of this pilot study was to determine if metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could serve as predictors of biochemical remission and pharmacotherapy-free interval in ...patients with metastatic pheochromocytomas (PCCs) and paragangliomas (PGLs).
Patients with metastatic PCCs/PGLs have a high rate of biochemical recurrence, which can be associated with increased cardiovascular morbidity. Predictors of biochemical response are needed to guide and select patients who may benefit from therapy.
Whole body MTV and TLG was calculated from preoperative 18F-FDG PET/CT scans and analyzed as marker of biochemical response and pharmacotherapy-free interval.
Seventeen patients underwent a total of 19 procedures, with a median follow-up time of 26.4 months. Whole body MTV of patients with biochemical recurrence (n = 13, mean 73.8 mL) was higher than those who had a biochemical response (n = 6, mean 14.7 mL, P = 0.05). Patients with low MTV (<37.2 mL) had an improved durable partial biochemical response (P < 0.05), and a statistical trend for complete biochemical remission (P = 0.07) and pharmacotherapy-free interval (P = 0.06). In 8 patients with metastatic disease outside the abdomen, 4 patients had less than 35% of their disease burden outside the abdomen and these patients had a more durable partial biochemical response compared to patients with greater than 35% of their disease burden outside the abdomen (P < 0.05).
Whole body MTV and TLG represents novel and valuable predictors of biochemical response for patients with metastatic PCCs and PGLs. A larger prospective study should be performed to validate these findings.
Background Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of ...prognosis. Objective The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. Methods Sixty-two patients with VHL-associated PNETs prospectively underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). MTV, TLG, and maximum standardized uptake value (SUVmax) were measured using a semi-automatic method. Surgically resected PNETs were classified according to 2010 World Health Organization tumor grade classification. MTV, TLG, and SUVmax were analyzed by metastatic disease and tumor grade using the Mann-Whitney test. Results A total of 88 PNETs were identified by CT and 18F-FDG PET/CT, 10 of which were non-FDG-avid. Histologic grading was available for 20 surgical patients. Patients with metastatic PNETs had a higher TLG (median 25.9 vs. 7.7 mean SUV SUVmean*mL; p = 0.0092) compared with patients without metastasis, while patients with grade 2 PNETs had a higher MTV (median 6.9 vs. 2.6 mL; p = 0.034) and TLG (median 41.2 vs. 13.1 SUVmean*mL; p = 0.0035) compared with patients with grade 1 PNETs. No difference in tumor size or SUVmax was observed between the groups. Conclusions Patients with metastatic PNETs have a higher TLG compared with patients without metastasis. Grade 2 PNETs have a higher MTV and TLG compared with grade 1 PNETs. Tumor size and SUVmax were not associated with grade. Volumetric parameters on 18F-FDG PET/CT may be useful in detecting higher grade PNETs with a higher malignant potential that may need surgical intervention.
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