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PURPOSE Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. METHODS Rats were split into three groups. In group 1 (N = 6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10 °C for 48 h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68 Ga-DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE-MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. RESULTS DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. CONCLUSION Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

Summary In rodents, lower brown adipose tissue (BAT) activity is associated with greater liver steatosis and changes in the gut microbiome. However, little is known about these relationships in humans. In adults (n = 60), we assessed hepatic fat and cold-stimulated BAT activity using magnetic resonance imaging and the gut microbiota with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity through the microbiota. Individuals with NAFLD (n = 29) have lower BAT activity than those without, and BAT activity is inversely related to hepatic fat content. BAT activity is not related to the characteristics of the fecal microbiota and is not transmissible through fecal transplantation to mice. Thus, low BAT activity is associated with higher hepatic fat accumulation in human adults, but this does not appear to have been mediated through the gut microbiota., Graphical abstract, Highlights Adults with NAFLD have lower brown adipose tissue activity compared with controls Brown adipose tissue (BAT) activity is not linked to fecal gut microbiota BAT activity is not transmissible to mice via fecal transplantation, Ahmed et al. show, using MRI, that higher cold-stimulated BAT activity is linked to lower hepatic fat in 60 adults. BAT activity is not linked to fecal gut microbiota characteristics and is not transmissible to germ-free mice. Gut microbiota does not link BAT activity and liver fat.

Context In rodents, cold exposure induces the activation of brown adipose tissue (BAT) and the induction of intracellular triacylglycerol (TAG) lipolysis. However, in humans, the kinetics of supraclavicular (SCV) BAT activation and the potential importance of TAG stores remain poorly defined. Objective To determine the time course of BAT activation and changes in intracellular TAG using MRI assessment of the SCV (i.e., BAT depot) and fat in the posterior neck region (i.e., non-BAT). Design Cross-sectional. Setting Clinical research center. Patients or Other Participants Twelve healthy male volunteers aged 18 to 29 years [body mass index = 24.7 ± 2.8 kg/m2 and body fat percentage = 25.0% ± 7.4% (both, mean ± SD)]. Intervention(s) Standardized whole-body cold exposure (180 minutes at 18°C) and immediate rewarming (30 minutes at 32°C). Main Outcome Measure(s) Proton density fat fraction (PDFF) and T2* of the SCV and posterior neck fat pads. Acquisitions occurred at 5- to 15-minute intervals during cooling and subsequent warming. Results SCV PDFF declined significantly after only 10 minutes of cold exposure [−1.6% (SE: 0.44%; P = 0.007)] and continued to decline until 35 minutes, after which time it remained stable until 180 minutes. A similar time course was also observed for SCV T2*. In the posterior neck fat (non-BAT), there were no cold-induced changes in PDFF or T2*. Rewarming did not result in a change in SCV PDFF or T2*. Conclusions The rapid cold-induced decline in SCV PDFF suggests that in humans BAT is activated quickly in response to cold and that TAG is a primary substrate.

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the beta(3)-adrenergic receptor (beta(3)-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of beta(3)-AR. Oral administration of the beta(3)-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to beta(1)-AR and beta(2)-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the beta(2)-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through beta(2)-AR signaling in humans (ClinicalTrials.gov NCT02811289).

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

Study Objectives Short sleep duration and sleep disturbances have been related to obesity and metabolic disruption. However, the behavioral and physiological mechanisms linking sleep and alterations in energy balance and metabolism are incompletely understood. In rodents, sleep regulation is closely related to appropriate brown adipose tissue (BAT) thermogenic activity, but whether the same is true in humans has remained unknown. The present work examines whether sleep duration and quality are related to BAT volume and activity (measured by 18F-FDG) and BAT radiodensity in humans. Methods A total of 118 healthy adults (69% women, 21.9 ± 2.2 years, body mass index: 24.9 ± 4.7 kg/m2) participated in this cross-sectional study. Sleep duration and other sleep variables were measured using a wrist-worn accelerometer for seven consecutive days for 24 hours per day. The Pittsburgh Sleep Quality Index was used to assess sleep quality. All participants then underwent a personalized cold exposure to determine their BAT volume, activity, and radiodensity (a proxy of the intracellular triglyceride content), using static positron emission tomography combined with computed tomography (PET/CI) scan. Results Neither sleep duration nor quality was associated with BAT volume or activity (the latter represented by the mean and peak standardized 18F-FDG uptake values) or radiodensity (all p > .1). The lack of association remained after adjusting the analyses for sex, date of PET/CT, and body composition. Conclusions Although experiments in rodent models indicate a strong relationship to exist between sleep regulation and BAT function, it seems that sleep duration and quality may not be directly related to the BAT variables examined in the present work. Clinical Trial Registration NCT02365129 (ClinicalTrials.gov).

KEY POINTS Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure. ABSTRACT We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18°C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10°C water circulating in liquid-conditioned suit, 2 h day-1 , 5 days week-1 ). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 °C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% (P

Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans.

In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and can metabolize large amounts of dietary fatty acids (DFA). The role of BAT in DFA metabolism in humans is unknown. Here we show that mild cold stimulation (18 °C) results in a significantly greater fractional DFA extraction by BAT relative to skeletal muscle and white adipose tissue in non-cold-acclimated men given a standard liquid meal containing the long-chain fatty acid PET tracer, 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA). However, the net contribution of BAT to systemic DFA clearance is comparatively small. Despite a 4-week cold acclimation increasing BAT oxidative metabolism 2.6-fold, BAT DFA uptake does not increase further. These findings show that cold-stimulated BAT can contribute to the clearance of DFA from circulation but its contribution is not as significant as the heart, liver, skeletal muscles or white adipose tissues.

The present study examines whether the daily rhythm of distal skin temperature (DST) is associated with brown adipose tissue (BAT) metabolism as determined by 18F-fluorodeoxyglucose (18F-FDG) uptake in young adults. Using a wireless thermometer (iButton) worn on the nondominant wrist, DST was measured in 77 subjects (26% male; age 22 ± 2 years; body mass index 25.2 ± 4.8 kg/m2) for 7 consecutive days. The temperatures to which they were habitually exposed over the day were also recorded. The interday stability of DST was calculated from the collected data, along with the intraday variability and relative amplitude; the mean temperature of the 5 and 10 consecutive hours with the maximum and minimum DST values, respectively; and when these hours occurred. Following exposure to cold, BAT volume and mean and peak standardized 18F-FDG uptake (SUVmean and SUVpeak) were determined for each subject via static 18F-FDG positron emission tomography/computed tomography scanning. Relative amplitude and the time at which the 10 consecutive hours of minimum DST values occurred were positively associated with BAT volume, SUVmean, and SUVpeak ( p ≤ 0.02), whereas the mean DST of that period was inversely associated with the latter BAT variables ( p ≤ 0.01). The interday stability and intraday variability of the DST were also associated (directly and inversely, respectively) with BAT SUVpeak ( p ≤ 0.02 for both). All of these associations disappeared, however, when the analyses were adjusted for the ambient temperature to which the subjects were habitually exposed. Thus, the relationship between the daily rhythm of DST and BAT activity estimated by 18F-FDG uptake is masked by environmental and likely behavioral factors. Of note is that those participants exposed to the lowest ambient temperature showed 3 to 5 times more BAT volume and activity compared with subjects who were exposed to a warmer ambient temperature.

The demonstration of the presence of metabolically active brown adipose tissue (BAT) in adult humans using positron emission tomography (PET) over the past decade has lead to the rapid development of our knowledge regarding the role of BAT in energy metabolism in animal models and in humans. Although animal models continue to provide highly valuable information regarding the mechanisms regulating BAT development, mass and metabolic functions, these studies led to many assumptions that have been at best only partially verified in humans so far. Combined to some limitations of the current investigation approaches used in humans, this has lead to speculation on the potential role of BAT dysfunction in the development of cardiometabolic disorders and on the potential of BAT metabolic activation to treat these conditions. Here we propose a critical review of the evidence for the implication of BAT in cardiometabolic health.

The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of 18F-fluorodeoxyglucose in combination with computed tomography (18F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative positron emission tomography and computed tomography (PET-CT) imaging strategies and radiotracers that may offer important insights. In addition to PET-CT, there are numerous emerging techniques that may have utility for assessing BAT metabolic activity including magnetic resonance imaging (MRI), skin temperature measurements, near-infrared spectroscopy (NIRS) and contrast ultrasound (CU). In this review, we discuss and critically evaluate the various methodologies used to measure BAT metabolic activity in humans and provide a contemporary assessment of protocols which may be useful in interpreting research findings and guiding the development of future studies.

The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques.

Spontaneous glucose uptake by brown adipose tissue (BAT) is lower in overweight or obese individuals and in diabetes. However, BAT metabolism has not been previously investigated in patients with type 2 diabetes during controlled cold exposure. Using positron emission tomography with 11C-acetate, 18F-fluoro-deoxyglucose (18FDG), and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, BAT oxidative metabolism and perfusion and glucose and nonesterified fatty acid (NEFA) turnover were determined in men with well-controlled type 2 diabetes and age-matched control subjects under experimental cold exposure designed to minimize shivering. Despite smaller volumes of 18FDG-positive BAT and lower glucose uptake per volume of BAT compared with young healthy control subjects, cold-induced oxidative metabolism and NEFA uptake per BAT volume and an increase in total body energy expenditure did not differ in patients with type 2 diabetes or their age-matched control subjects. The reduction in 18FDG-positive BAT volume and BAT glucose clearance were associated with a reduction in BAT radiodensity and perfusion. 18FDG-positive BAT volume and the cold-induced increase in BAT radiodensity were associated with an increase in systemic NEFA turnover. These results show that cold-induced NEFA uptake and oxidative metabolism are not defective in type 2 diabetes despite reduced glucose uptake per BAT volume and BAT “whitening.”

Key points Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. Abstract Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-13C]-palmitate and [3-3H]-glucose tracer methodologies coupled with positron emission tomography using 11C-acetate and 18F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min−1, respectively, P

As endotherms, humans exposed to a compensable cold environment rely on an increase in thermogenic rate to counteract heat lost to the environment, thereby maintaining a stable core temperature. This review focuses primarily on the most important contributor of heat production in cold-exposed adult humans, shivering skeletal muscles. Specifically, it presents current understanding on (1) the origins of shivering, (2) the contribution of shivering to total heat production and (3) the metabolic requirements of shivering. Although shivering had commonly been measured as a metabolic outcome measure, considerable research is still needed to clearly identify the neuroanatomical structures and circuits that initiate and modulate shivering and drives the shivering patterns (continuous and burst shivering). One thing is clear, the thermogenic rate in humans can be maintained despite significant inter-individual differences in the thermogenic contribution of shivering, the muscles recruited in shivering, the burst shivering rate and the metabolic substrates used to support shivering. It has also become evident that the variability in burst shivering rate between individuals, despite not influencing heat production, does play a key role in orchestrating metabolic fuel selection in the cold. In addition, advances in our understanding of the thermogenic role of brown adipose tissue have been able to explain, at least in part, the large inter-individual differences in the contribution of shivering to total heat production. Whether these differences in the thermogenic role of shivering have any bearing on cold endurance and survival remains to be established. Despite the available research describing the relative thermogenic importance of shivering skeletal muscles in humans, the advancement in our understanding of how shivering is initiated and modulated is needed. Such research is critical to consider strategies to either reduce its role to improve occupational performance or exploit its metabolic potential for clinical purposes.

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.

In cold exposed humans, increasing thermogenic rate is essential to prevent decreases in core temperature. This review describes the metabolic requirements of thermogenic pathways, mainly shivering thermogenesis, the largest contributor of heat. Research has shown that thermogenesis is sustained from a combination of carbohydrates, lipids, and proteins. The mixture of fuels is influenced by shivering intensity and pattern as well as by modifications in energy reserves and nutritional status. To date, there are no indications that differences in the types of fuel being used can alter shivering and overall heat production. We also bring forth the potential contribution of nonshivering thermogenesis in adult humans via the activation of brown adipose tissue (BAT) and explore some means to stimulate the activity of this highly thermogenic tissue. Clearly, the potential role of BAT, especially in young lean adults, can no longer be ignored. However, much work remains to clearly identify the quantitative nature of this tissue's contribution to total thermogenic rate and influence on shivering thermogenesis. Identifying ways to potentiate the effects of BAT via cold acclimation and/or the ingestion of compounds that stimulate the thermogenic process may have important implications in cold endurance and survival.

Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes, which may have important pathological and therapeutic implications. Although many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: Our objective was to determine whether 4 weeks of daily cold exposure could increase both the volume of metabolically active BAT and its oxidative capacity. Design: Six nonacclimated men were exposed to 10°C for 2 hours daily for 4 weeks (5 d/wk), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with [11C]acetate and [18F]fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake, and volume before and after 4 weeks of cold acclimation were examined under controlled acute cold-exposure conditions. Results: The 4-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66 ± 30 to 95 ± 28 mL, P < .05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725 ± 0.300 to 1.591 ± 0.326 mL·s−1, P < .05). Shivering intensity was not significantly different before compared with after acclimation (2.1% ± 0.7% vs 2.0% ± 0.5% maximal voluntary contraction, respectively). Fractional glucose uptake in BAT increased after acclimation (from 0.035 ± 0.014 to 0.048 ± 0.012 min−1), and net glucose uptake also trended toward an increase (from 163 ± 60 to 209 ± 50 nmol·g−1·min−1). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.