Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.

Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Automated segmentation of the human supraclavicular fat depot via deep neural network in water-fat separated magnetic resonance images.

Background: Human brown adipose tissue (BAT), mostly located in the cervical/supraclavicular region, is a promising target in obesity treatment. Magnetic resonance imaging (MRI) allows for mapping the fat content quantitatively. However, due to the complex heterogeneous distribution of BAT, it has been difficult to establish a standardized segmentation routine based on magnetic resonance (MR) images. Here, we suggest using a multi-modal deep neural network to detect the supraclavicular fat pocket. Methods: A total of 50 healthy subjects [median age/body mass index (BMI) =36 years/24.3 kg/m2] underwent MRI scans of the neck region on a 3 T Ingenia scanner (Philips Healthcare, Best, Netherlands). Manual segmentations following fixed rules for anatomical borders were used as ground truth labels. A deep learning-based method (termed as BAT-Net) was proposed for the segmentation of BAT on MRI scans. It jointly leveraged two-dimensional (2D) and three-dimensional (3D) convolutional neural network (CNN) architectures to efficiently encode the multi-modal and 3D context information from multi-modal MRI scans of the supraclavicular region. We compared the performance of BAT-Net to that of 2D U-Net and 3D U-Net. For 2D U-Net, we analyzed the performance difference of implementing 2D U-Net in three different planes, denoted as 2D U-Net (axial), 2D U-Net (coronal), and 2D U-Net (sagittal). Results: The proposed model achieved an average dice similarity coefficient (DSC) of 0.878 with a standard deviation of 0.020. The volume segmented by the network was smaller compared to the ground truth labels by 9.20 mL on average with a mean absolute increase in proton density fat fraction (PDFF) inside the segmented regions of 1.19 percentage points. The BAT-Net outperformed all implemented 2D U-Nets and the 3D U-Nets with average DSC enhancement ranging from 0.016 to 0.023. Conclusions: The current work integrates a deep neural network-based segmentation into the automated segmentation of supraclavicular fat depot for quantitative evaluation of BAT. Experiments show that the presented multi-modal method benefits from leveraging both 2D and 3D CNN architecture and outperforms the independent use of 2D or 3D networks. Deep learning-based segmentation methods show potential towards a fully automated segmentation of the supraclavicular fat depot.

Thermogenic Capacity of Human Supraclavicular Brown Fat and Cold-Stimulated Brain Glucose Metabolism.

Human brain metabolism is susceptible to temperature changes. It has been suggested that the supraclavicular brown adipose tissue (BAT) protects the brain from these fluctuations by regulating heat production through the presence of uncoupling protein 1 (UCP-1). It remains unsolved whether inter-individual variation in the expression of UCP-1, which represents the thermogenic capacity of the supraclavicular BAT, is linked with brain metabolism during cold stress. Ten healthy human participants underwent 18F-FDG PET scanning of the brain under cold stimulus to determine brain glucose uptake (BGU). On a separate day, an excision biopsy of the supraclavicular fat-the fat proximal to the carotid arteries supplying the brain with warm blood-was performed to determine the mRNA expression of the thermogenic protein UCP-1. Expression of UCP-1 in supraclavicular BAT was directly related to the whole brain glucose uptake rate determined under cold stimulation (rho = 0.71, p = 0.03). In sub-compartmental brain analysis, UCP-1 expression in supraclavicular BAT was directly related to cold-stimulated glucose uptake rates in the hypothalamus, medulla, midbrain, limbic system, frontal lobe, occipital lobe, and parietal lobe (all rho ≥ 0.67, p < 0.05). These relationships were independent of body mass index and age. When analysing gene expressions of BAT secretome, we found a positive correlation between cold-stimulated BGU and DIO2. These findings provide evidence of functional links between brain metabolism under cold stimulation and UCP-1 and DIO2 expressions in BAT in humans. More research is needed to evaluate the importance of these findings in clinical outcomes, for instance, in examining the supporting role of BAT in cognitive functions under cold stress.

Regulation of Brown Adipose Tissue Activity by Interoceptive CNS Pathways: The interaction between Brain and Periphery.

To maintain thermal homeostasis, specific thermogenic tissues are under the control of central thermoregulatory networks that regulate the body's response to thermal challenges. One of these mechanisms involves non-shivering thermogenesis in brown adipose tissue (BAT), which is activated in cold environments in order to defend the body against physical damage as a result of hypothermia. The objective of our study was to assess the interaction between CNS thermoregulatory pathways and sympathetic innervation in BAT during a cold exposure paradigm. Our results show that an innocuous whole-body cooling paradigm induces significant differences in fMRI BOLD signal at the location of the right anterior insula and the red nucleus/substantia nigra region, between lean subjects with high levels of sympathetic innervation in supraclavicular BAT (BAT+ group), and subjects with low levels of sympathetic innervation (BAT- group). Specifically, results indicate significantly larger fMRI BOLD signal changes between periods of cooling and warming of the skin in the BAT+ (as compared to BAT-) group at the location of the right anterior insula. In contrast, the BAT+ group showed significantly smaller fMRI BOLD signal changes in the midbrain between periods of skin cooling and warming. Our findings are consistent with a hierarchical thermoregulatory control system that involves the initiation of inhibitory signals from the right anterior insula toward midbrain areas that normally exert tonic inhibition on the medullary raphe, from where BAT is directly innervated. Our data suggests that exposure to cold elicits differential neuronal activity in interoceptive regulatory centers of subjects with high and low level of sympathetic innervation. As a result, the variability of cold-activated BAT mass observed in humans might be, in part, yoked to different sensitivities of interoceptive cortical brain areas to skin temperature changes.

Common and distinct regulation of human and mouse brown and beige adipose tissues: a promising therapeutic target for obesity.

Obesity, which underlies various metabolic and cardiovascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the current obesity epidemic, there is a pressing need for more novel therapeutic strategies that will help adult individuals to manage their weight. One promising therapeutic intervention for reducing obesity is to enhance energy expenditure. Investigations into human brown fat and the recently discovered beige/brite fat have galvanized intense research efforts during the past decade because of their pivotal roles in energy dissipation. In this review, we summarize the evolution of human brown adipose tissue (hBAT) research and discuss new in vivo methodologies for evaluating energy expenditure in patients. We highlight the differences between human and mouse BAT by integrating and comparing their cellular morphology, function, and gene expression profiles. Although great advances in hBAT biology have been achieved in the past decade, more cellular models are needed to acquire a better understanding of adipose-specific processes and molecular mechanisms. Thus, this review also describes the development of a human brown fat cell line, which could provide promising mechanistic insights into hBAT function, signal transduction, and development. Finally, we focus on the therapeutic potential and current limitations of hBAT as an anti-glycemic, anti-lipidemic, and weight loss-inducing 'metabolic panacea'.

Glucagon increases energy expenditure independently of brown adipose tissue activation in humans.

AIMS: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans. METHODS: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on (18)F-FDG PET/CT (n = 8) underwent a randomly allocated second (18)F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4). RESULTS: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on (18)F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not. CONCLUSIONS: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.

Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand.

INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7kg/m(2); 5 F: age 25.4±2.1, BMI 22.1±1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.