Brown Adipose Tissue Perfusion Research Articles

Molecular Tuning of IR-786 for Improved Brown Adipose Tissue Imaging.

To overcome the limitations of brown adipose tissue (BAT) imaging with MRI and PET/CT, near-infrared (NIR) fluorescence imaging has been utilized in living animals because it is highly sensitive, noninvasive, nonradioactive, and cost-effective. To date, only a few NIR fluorescent dyes for detecting BAT have been reported based on the structure-inherent targeting strategy. Among them, IR-786, a commercial cyanine dye, was used firstly for quantitative NIR imaging of BAT perfusion in 2003. Owing to the high cytotoxicity, poor water solubility, and strong nonspecific background uptake of IR-786, the chemical structure of IR-786 should be redesigned to be more hydrophilic and less toxic so that it can show more BAT-specific accumulation. Here, we developed a BAT-specific NIR dye, BF800-AM, by incorporating the tyramine linker in the original structure of IR-786. After modifying the physicochemical properties of IR-786, in vivo results showed significant uptake of the newly designed BF800-AM in the BAT with improved signal-to-background ratio. Additional in vivo studies using mouse tumor models revealed that BF800-AM targeting to BAT is independent of tumor tissues, as distinct from IR-786 showing uptake in both tissues. Therefore, BF800-AM can be used for improved noninvasive visualization of BAT mass and activity in living animals.

Xenon-enhanced computed tomography assessment of brown adipose tissue distribution and perfusion in lean, obese, and diabetic primates.

ObjectiveThis study aimed to validate xenon‐enhanced computed tomography (XECT) for the detection of brown adipose tissue (BAT) and to use XECT to assess differences in BAT distribution and perfusion between lean, obese, and diabetic nonhuman primates (NHPs).MethodsWhole‐body XECT imaging was performed in anesthetized rhesus and vervet monkeys during adrenergic stimulation of BAT thermogenesis. In XECT images, BAT was identified as fat tissue that, during xenon inhalation, underwent significant radiodensity enhancement compared with subcutaneous fat. To measure BAT blood flow, BAT radiodensity enhancement was measured over time on the six computed tomography scans acquired during xenon inhalation. Postmortem immunohistochemical staining was used to confirm imaging findings.ResultsXECT was able to correctly identify all BAT depots that were confirmed at necropsy, enabling construction of the first comprehensive anatomical map of BAT in NHPs. A significant decrease in BAT perfusion was found in diabetic animals compared with obese animals and healthy animals, as well as absence of axillary BAT and significant reduction of supraclavicular BAT in diabetic animals compared with obese and lean animals.ConclusionsThe use of XECT in NHP models of obesity and diabetes allows the analysis of the impact of metabolic status on BAT mass and perfusion.

Secretin activates brown fat and induces satiation.

Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut-BAT-brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [18F]FDG and [15O]H2O positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) μmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (-2.91, 0.07), P = 0.063, effect size d = -0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.

Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis.

Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen and for the distribution of the generated heat to the rest of the body. Therefore, it is fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here, we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel noninvasive method to detect BAT perfusion, we demonstrate that adrenergically stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and therefore, it is not a reliable parameter for the estimation of BAT activation and heat generation.

Hyperthyroidism Increases Brown Fat Metabolism in Humans

Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. This was a follow-up study using positron emission tomography imaging. Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.

Abstract 16795: Detection of Brown Adipose Tissue Activation and Mass Using Contrast Ultrasound

Obesity is an increasingly frequent condition and a risk factor for cardiovascular diseases. Brown adipose tissue (BAT), located mostly in the paravertebral and supraclavicular space in humans and between the scapulae in rodents, consumes lipids and glucose to produce heat when it is activated by norepinephrine (NE) or cold. Increasing metabolic activity and/or mass of BAT could open new therapeutic avenues to treat obesity. Currently,18F-fluorodeoxyglucose Positron Emission Tomography is the only imaging technique detecting BAT and its activation in humans. Since increased BAT blood flow is associated with BAT activation, we hypothesized that BAT contrast ultrasound (CU) could estimate the degree of BAT activation and BAT mass, both in mice and humans. To validate the ability of CU to estimate BAT perfusion, the BAT and kidney of C57BL6 wild type mice were imaged with a 14 MHz linear transducer during continuous infusion of DefinityTM microbubble contrast. The time intensity curves of the contrast were quantified and blood flow was estimated by the product of the curve plateau A and slope ß. The BAT/kidney blood flow ratio obtained with CU was compared to that measured with fluorescent microspheres. In another experiment, to validate the ability of CU to estimate BAT mass, the maximal area of perfusion of BAT was compared to the BAT weight, in mice. Finally, the BAT vascular response to activation was assessed in 6 mice before and after infusing 1µg/kg/min NE and in 7 young and lean human volunteers before and after cold exposure (16°C for 2 hours).The BAT/kidney blood flow ratio obtained by CU in mice correlated with microsphere measurements (R2=0.85, p&lt;0.05). The maximal area of BAT measured by CU correlated with BAT weight (R2=0.58, p&lt;0.002). Mice demonstrated a 10-fold increase in BAT perfusion after infusion of NE (Aß 0.6±0.1 vs. 5.5±0.9 dB/s, p&lt;0.05) while kidney perfusion decreased. Similarly, BAT perfusion increased in humans after cold exposure (Aß 0.1±0.0 vs. 1.0±0.4 dB/s,p&lt;0.05). In conclusion, contrast ultrasound imaging can be used to estimate BAT activation and its mass. This noninvasive technique free of ionizing radiation offers a method for serial evaluation and monitoring of therapies designed to activate BAT or augment its mass.

Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner.

Blood flow to the brown adipose tissue of conscious young rabbits during hypoxia in cold and warm conditions.

Brown adipose tissue (BAT) non-shivering thermogenesis is stimulated by cold temperature and depressed by hypoxia. We investigated the extent to which changes in metabolic rate during cold and hypoxia, singly or combined, were accompanied by changes in BAT perfusion. One-month-old rabbits were instrumented for measurements of regional blood flow by the coloured microsphere technique. One group of rabbits was tested in warm (24 degrees C, n=17), and the other in cold (13 degrees C, n=9) conditions, first in normoxia (inspired oxygen concentration FIO2 about 21%, arterial oxygen saturation SaO2 approximately 88%) followed by hypoxia (FIO2 approximately 10%, SaO2 approximately 54%). In warm conditions, oxygen consumption (VO2, measured by an open-flow method) averaged 22 ml.kg-1.min-1 (STPD), and BAT blood flow 98 ml.100g-1.min-1. In hypoxia, VO2 dropped on average to 87%, whereas BAT flow dropped to 43% of the normoxic values. In the cold during normoxia, VO2 averaged 31 ml.kg-1.min-1 (STPD), and BAT blood flow was 155 ml.100g-1.min-1. In cold and hypoxia VO2 dropped to 19 ml.kg-1.min-1 (STPD) (i.e. 60% of the normoxic value), whereas BAT blood flow was not altered significantly (148 ml.100g-1.min-1). Hence, BAT blood flow decreased in hypoxia in absence of cold stimuli, whereas it remained high when hypoxia occurred during cold, despite the major drop in VO2. We conclude that cold is more important than hypoxia in determining BAT perfusion, and that changes in BAT blood flow are not a mechanism for the hypoxic control of V.O2.