Genetic evidence for involvement of ß2-adrenergic receptor in brown adipose tissue thermogenesis in humans.

BACKGROUND: Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the ß-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding ß-ARs and BAT activity in human adults. METHODS: Single nucleotide polymorphisms (SNPs) in ß1-, ß2-, and ß3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber. RESULTS: We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits. CONCLUSIONS: The present study supports the importance of ß2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Brown fat-associated postprandial thermogenesis in humans: Different effects of isocaloric meals rich in carbohydrate, fat, and protein.

The increase of whole-body energy expenditure seen after a single meal ingestion, referred to as diet-induced thermogenesis (DIT), substantially varies depending on the meal's macronutrient composition. Brown adipose tissue (BAT), a site of non-shivering thermogenesis, was reported to be involved in DIT. To examine the effects of meal composition on BAT-associated DIT in humans, healthy male participants underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity, and respiratory gas analysis for 2 h after ingestion of a carbohydrate-, protein-, or fat-rich meal (C-meal, P-meal, and F-meal, respectively). The calculated DIT at 2 h was 6.44 ± 2.01%, 3.49 ± 2.00%, and 2.32 ± 0.90% of the ingested energy after the P-meal, C-meal, and F-meal, respectively. The DIT after C-meal ingestion correlated positively with BAT activity (P = 0.011), and was approximately twice greater in the group with high-BAT activity than in the group with low-BAT activity (4.35 ± 1.74% vs. 2.12 ± 1.76%, P < 0.035). Conversely, the DIT after F-meal or P-meal ingestion did not correlate with BAT activity, with no difference between the two groups. Thus, BAT has a significant role in DIT after ingestion of a carbohydrate-rich meal, but hardly after ingestion either protein- or fat-rich meal.

Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.

Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans. Physiological cold exposure downregulates Selenop in BAT. Selenop knockout mice show higher rectal temperatures and UCP1 sulfenylation during cold exposure. SeP treatment to brown adipocytes eliminated the NA-induced mitochondrial ROS by upregulating glutathione peroxidase 4 and impaired cellular thermogenesis. A high-fat/high-sucrose diet elevates serum SeP levels and diminishes the elevated NA-induced thermogenesis in BAT-Selenop KO mice. Therefore, SeP is the intrinsic factor inducing reductive stress that impairs thermogenesis in BAT and may be a potential therapeutic target for obesity and diabetes.

Diurnal variations of brown fat thermogenesis and fat oxidation in humans.

BACKGROUND/OBJECTIVES: Disturbed circadian rhythm is associated with an increased risk of obesity and metabolic disorders. Brown adipose tissue (BAT) is a site of nonshivering thermogenesis (NST) and plays a role in regulating whole-body energy expenditure (EE), substrate metabolism, and body fatness. In this study, we examined diurnal variations of NST in healthy humans by focusing on their relation to BAT activity. METHODS: Forty-four healthy men underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography and were divided into Low-BAT and High-BAT groups. In STUDY 1, EE, diet-induced thermogenesis (DIT), and fat oxidation (FO) were measured using a whole-room indirect calorimeter at 27 °C. In STUDY 2, EE, FO, and skin temperature in the region close to BAT depots (Tscv) and in the control region (Tc) were measured at 27 °C and after 90 min cold exposure at 19 °C in the morning and in the evening. RESULTS: In STUDY 1, DIT and FO after breakfast was higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. FO in the High-BAT group was higher after breakfast than after dinner (P < 0.01). In STUDY 2, cold-induced increases in EE (CIT), FO, and Tscv relative to Tc in the morning were higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. CIT in the High-BAT group tended to be higher in the morning than in the evening (P = 0.056). CONCLUSION: BAT-associated NST and FO were evident in the morning, but not in the evening, suggesting that the activity of human BAT is higher in the morning than in the evening, and thus may be involved in the association of an eating habit of breakfast skipping with obesity and related metabolic disorders.

Prolonged Treatment with Grains of Paradise (Aframomum melegueta) Extract Recruits Adaptive Thermogenesis and Reduces Body Fat in Humans with Low Brown Fat Activity.

Increasing adaptive thermogenesis through the activation of brown adipose tissue (BAT) is a promising practical strategy for preventing obesity and related disorders. Ingestion of a single dose of 40 mg of an extract of Grains of Paradise (GP), a ginger family species, reportedly triggers BAT thermogenesis in individuals with high but not in those with low BAT activity. We hypothesized that prolonged treatment with GP might revive BAT in individuals who have lost active BAT. In the present study, we recruited 9 healthy young male volunteers with reduced BAT that was assessed by fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) following 2-h cold exposure at 19ºC. The subjects ingested GP extract (40 mg/d) or placebo every day for 5 wk. Before and after the treatment with either GP or placebo, their body composition and BAT-dependent cold-induced thermogenesis (CIT)-a non-invasive index of BAT-were measured in a single-blinded, randomized, placebo-controlled cross-over design. Their whole-body resting energy expenditure at a thermoneutral condition remained unchanged following GP treatment. However, CIT after treatment was significantly higher in GP-treated individuals than in placebo-treated individuals. Body weight and fat-free mass did not change significantly following GP or placebo treatment. Notably, body fat percentage slightly but significantly decreased after GP treatment but not after placebo treatment. These results suggest that repeated ingestion of GP elevates adaptive thermogenesis through the re-activation of BAT, thereby reducing body fat in individuals with low BAT activity.

Multiorgan contribution to non-shivering and shivering thermogenesis and vascular responses during gradual cold exposure in humans.

PURPOSE: Human brown adipose tissue (BAT) is known to be a significant thermoeffector in non-shivering thermogenesis (NST), albeit with individual variations in the BAT activity. We hypothesized that humans with less BAT would have more contribution from the skeletal muscle (SM) to NST or earlier shivering onset and greater vasoconstriction to compensate for less BAT-mediated thermogenesis. METHODS: Eighteen males participated in this study. Their BAT activity and detectable volume were investigated. A gradual cold exposure was conducted for inducing NST at 18.6 °C and initiating shivering at 11.6 °C. The energy expenditure, electromyograph of the pectoralis major, skin blood flow, and rectal (Tre) and skin temperatures were evaluated. RESULTS: BAT volume significantly correlated with the change in metabolic heat production during mild cold phase relative to baseline (NST; r = 0.562, P < 0.05), but not with shivering initiation phase (NST+ ST). SM mass correlated with baseline metabolic heat production (Mbase; r = 0.839, P < 0.01) but not with NST or NST + ST. A positive correlation was noted between BAT volume and Tre at the end of the 18.6 °C exposure period (r = 0.586, P < 0.05), which positively correlated with shivering onset time (r = 0.553, P < 0.05). The skin blood flow, mean skin temperature, and forearm and finger skin temperature difference at the end of the 18.6 °C exposure period did not correlate with NST or BAT volume. CONCLUSION: BAT volume positively correlated with NST. Notably, lower Tre in individuals with less BAT volume induced earlier shivering onset for offsetting the less NST. Whereas, no correlation between metabolic and vasomotor responses was observed.

Near-Infrared Time-Resolved Spectroscopy for Assessing Brown Adipose Tissue Density in Humans: A Review.

Brown adipose tissue (BAT) mediates adaptive thermogenesis upon food intake and cold exposure, thus potentially contributing to the prevention of lifestyle-related diseases. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) with computed tomography (CT) (18FDG-PET/CT) is a standard method for assessing BAT activity and volume in humans. 18FDG-PET/CT has several limitations, including high device cost and ionizing radiation and acute cold exposure necessary to maximally stimulate BAT activity. In contrast, near-infrared spectroscopy (NIRS) has been used for measuring changes in O2-dependent light absorption in the tissue in a non-invasive manner, without using radiation. Among NIRS, time-resolved NIRS (NIRTRS) can quantify the concentrations of oxygenated and deoxygenated hemoglobin ([oxy-Hb] and [deoxy-Hb], respectively) by emitting ultrashort (100 ps) light pulses and counts photons, which are scattered and absorbed in the tissue. The basis for assessing BAT density (BAT-d) using NIRTRS is that the vascular density in the supraclavicular region, as estimated using Hb concentration, is higher in BAT than in white adipose tissue. In contrast, relatively low-cost continuous wavelength NIRS (NIRCWS) is employed for measuring relative changes in oxygenation in tissues. In this review, we provide evidence for the validity of NIRTRS and NIRCWS in estimating human BAT characteristics. The indicators (IndNIRS) examined were [oxy-Hb]sup, [deoxy-Hb]sup, total hemoglobin [total-Hb]sup, Hb O2 saturation (StO2sup), and reduced scattering coefficient ( µs sup' ) in the supraclavicular region, as determined by NIRTRS, and relative changes in corresponding parameters, as determined by NIRCWS. The evidence comprises the relationships between the IndNIRS investigated and those determined by 18FDG-PET/CT; the correlation between the IndNIRS and cold-induced thermogenesis; the relationship of the IndNIRS to parameters measured by 18FDG-PET/CT, which responded to seasonal temperature fluctuations; the relationship of the IndNIRS and plasma lipid metabolites; the analogy of the IndNIRS to chronological and anthropometric data; and changes in the IndNIRS following thermogenic food supplementation. The [total-Hb]sup and [oxy-Hb]sup determined by NIRTRS, but not parameters determined by NIRCWS, exhibited significant correlations with cold-induced thermogenesis parameters and plasma androgens in men in winter or analogies to 18FDG-PET. We conclude that NIRTRS can provide useful information for assessing BAT-d in a simple, rapid, non-invasive way, although further validation study is still needed.

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men.

Since the recent rediscovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has been attracting increasing interest. The inverse relationship between BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential (TRP) channels and the sympathetic nervous system (SNS). Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP-SNS-BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis (DIT), which is a significant component of the total energy expenditure in our daily lives. Emerging evidence suggests a crucial role for the SNS in BAT-associated DIT, particularly during the early phase, but several gut-derived humoral factors may also participate in meal-induced BAT activation. One intriguing factor is bile acids, which activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes. Given the apparent beneficial effects of some TRP agonists and bile acids on whole-body substrate and energy metabolism, the TRP/TGR5-BAT axis represents a promising target for combating obesity and related metabolic disorders in humans.

Association of circulating exosomal miR-122 levels with BAT activity in healthy humans.

Brown adipose tissue (BAT) plays an important role in body fat accumulation and the regulation of energy expenditure. Since the role of miRNAs in the pathogenesis of obesity and related metabolic diseases is contentious, we analyzed exosomal miRNAs in serum of healthy subjects with special references to BAT activity and body fat level. Forty male volunteers aged 20-30 years were recruited. Their BAT activity was assessed by fluorodeoxyglucose positron emission tomography and computed tomography after 2 h of cold exposure and expressed as a maximal standardized uptake value (SUVmax). Exosomal miRNA levels was analyzed using microarray and real-time PCR analyses. The miR-122-5p level in the high BAT activity group (SUV ≧ 3) was 53% lower than in the low BAT activity group (SUVmax <3). Pearson's correlation analysis revealed that the serum miR-122-5p level correlated negatively with BAT activity and the serum HDL-cholesterol, and it correlated positively with age, BMI, body fat mass, and total cholesterol and triglyceride serum levels. Multivariate regression analysis revealed that BAT activity was associated with the serum miR-122-5p level independently of the other parameters. These results reveal the serum exosomal miR-122-5p level is negatively associated with BAT activity independently of obesity.

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

An optimal condition for the evaluation of human brown adipose tissue by infrared thermography.

Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis and is an attractive therapeutic target for combating obesity and related diseases. Human BAT activity has been evaluated by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) under acute cold exposure, but the method has some serious limitations, including radiation exposure. Infrared thermography (IRT) may be a simple and less-invasive alternative to evaluate BAT activity. In the present study, to establish an optimal condition for IRT, using a thermal imaging camera, skin temperature was measured in the supraclavicular region close to BAT depots (Tscv) and the control chest region (Tc) in 24 young healthy volunteers. Their BAT activity was assessed as the maximal standardized uptake value (SUVmax) by 18FDG-PET/CT. Under a warm condition at 24-27°C, no significant correlation was found between the IRT parameters (Tscv, Tc,, and the difference between Tscv and Tc,, Δtemp) and SUVmax, but 30-120 min after cold exposure at 19°C, Tscv and Δtemp were significantly correlated with SUVmax (r = 0.40-0.48 and r = 0.68-0.76). Δtemp after cold exposure was not affected by mean body temperature, body fatness, and skin blood flow. A lower correlation (r = 0.43) of Δtemp with SUVmax was also obtained when the participant's hands were immersed in water at 18°C for 5 min. Receiver operating characteristic analysis revealed that Δtemp after 30-60 min cold exposure can be used as an index for BAT evaluation with 74% sensitivity, 92% specificity, and 79% diagnostic accuracy. Thus, IRT may be useful as a simple and less-invasive method for evaluating BAT, particularly for large-scale screening and longitudinal repeat studies.

Applicability of Supraclavicular Oxygenated and Total Hemoglobin Evaluated by Near-Infrared Time-Resolved Spectroscopy as Indicators of Brown Adipose Tissue Density in Humans.

Brown adipose tissue (BAT) may potentially be used in strategies for preventing lifestyle-related diseases. We examine evidence that near-infrared time-resolved spectroscopy (NIRTRS) is capable of estimating human BAT density (BAT-d). The parameters examined in this study are total hemoglobin [total-Hb]sup, oxygenated Hb [oxy-Hb]sup, deoxygenated Hb [deoxy-Hb]sup, Hb O2 saturation (StO2sup), and the reduced scattering coefficient in the supraclavicular region (µs'sup), where BAT deposits can be located; corresponding parameters in the control deltoid region are obtained as controls. Among the NIRTRS parameters, [total-Hb]sup and [oxy-Hb]sup show region-specific increases in winter, compared to summer. Further, [total-Hb]sup and [oxy-Hb]sup are correlated with cold-induced thermogenesis in the supraclavicular region. We conclude that NIRTRS-determined [total-Hb]sup and [oxy-Hb]sup are useful parameters for evaluating BAT-d in a simple, rapid, non-invasive manner.

Translational Aspects of Brown Fat Activation by Food-Derived Stimulants.

Since the rediscovery of brown adipose tissue (BAT) in humans, its energy-dissipating ability has been well-recognized. The negative correlations of BAT activity with adiposity and insulin sensitivity provided an obvious rationale for discerning reliable and practical strategies for stimulating BAT. Though cold exposure or use of pharmacological adrenomimetics can activate BAT, they may have adverse effects. Therefore, determining alternative stimulants of BAT with lower risks such as commonly used food ingredients is highly desirable. Recent observations revealed that chemical activation of temperature-sensitive transient receptor potential (TRP) channels by food ingredients can recruit BAT in humans. Furthermore, animal studies have identified several food-derived stimulants of BAT acting through multiple mechanisms distinct from a TRP-mediated process. Dietary compounds acting as an activator of Sirtuin 1, a critical regulator of mitochondrial biogenesis and brown adipocyte differentiation, are one such class of promising food-derived BAT activators in humans. While the individual effects of various dietary factors are increasingly established in a laboratory setting, the potential synergistic effects of multiple stimulants on BAT remain to be tested in a clinical environment. These investigations may support the development of efficient, flexible dietary regimens capable of boosting BAT thermogenesis.

Brown adipose tissue density measured by near-infrared time-resolved spectroscopy in Japanese, across a wide age range.

F18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) along with computed tomography (CT) is a standard method for assessing brown adipose tissue (BAT) activity. We tested the usefulness of near-infrared time-resolved spectroscopy (NIRTRS) as a simple and noninvasive method for evaluating BAT density (BAT-d) by examining the effects of some factors known to influence BAT activity. The total hemoglobin concentration as a parameter of BAT-d was evaluated using NIRTRS in the supraclavicular region in 413 Japanese individuals. The associations were analyzed between BAT-d and sex, age, the percentages of body fat (%BF), visceral fat (VF), and the seasonal ambient temperature (AmT) fluctuations. Age was associated with decreased BAT-d (P < 0.05). There was no sex difference in the BAT-d, except for those in their twenties. Multivariate analyses revealed that %BF and VF were correlated with BAT-d, and the lower AmT (around 4°C or 5°C) for 4 and 6 weeks prior to the measurement day was associated with an increase in the BAT-d. Our NIRTRS results were analogous to those reported with FDG18-PET / CT, indicating the usefulness of NIRTRS. BAT-d might increase during the 4 and 6 weeks after the AmT decreases to lower than 4°C or 5°C.

Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans.

Background: The thermogenic effects of green tea catechin have been repeatedly reported, but their mechanisms are poorly understood.Objective: The aim of this study was to investigate the acute and chronic effects of catechin on brown adipose tissue (BAT), a site specialized for nonshivering thermogenesis, in humans.Design: Fifteen healthy male volunteers underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity. To examine the acute catechin effect, whole-body energy expenditure (EE) after a single oral ingestion of a beverage containing 615 mg catechin and 77 mg caffeine (catechin beverage) was measured. Next, to investigate the chronic catechin effects, 10 men with low BAT activity were enrolled. Before and after ingestion of the catechin beverage 2 times/d for 5 wk, cold-induced thermogenesis (CIT) after 2 h of cold exposure at 19°C, which is proportional to BAT activity, was examined. Both the acute and chronic trials were single-blinded, randomized, placebo-controlled, season-matched crossover studies.Results: A single ingestion of the catechin beverage increased EE in 9 subjects who had metabolically active BAT (mean ± SEM: +15.24 ± 1.48 kcal, P < 0.01) but not in 6 subjects who had negligible activities (mean ± SEM: +3.42 ± 2.68 kcal). The ingestion of a placebo beverage containing 82 mg caffeine produced a smaller and comparative EE response in the 2 subject groups. Multivariate regression analysis revealed a significant interaction between BAT and catechin on EE (ß = 0.496, P = 0.003). Daily ingestion of the catechin beverage elevated mean ± SEM CIT (from 92.0 ± 26.5 to 197.9 ± 27.7 kcal/d; P = 0.009), whereas the placebo beverage did not change it.Conclusion: Orally ingested tea catechin with caffeine acutely increases EE associated with increased BAT activity and chronically elevates nonshivering CIT, probably because of the recruitment of BAT, in humans. These trials were registered at www.umin.ac.jp/ctr/ as UMIN000016361.

Activation and recruitment of brown adipose tissue by cold exposure and food ingredients in humans.

Since the recent re-discovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has attracted increasing interest. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT in association with increased energy expenditure and decreased body fatness. The stimulatory effects of cold are mediated through transient receptor potential channels (TRP), most of which are also chemesthetic receptors for various food ingredients. In fact, capsaicin and its analog capsinoids, representative agonists of TRPV1, mimic the effects of cold to decrease body fatness through the activation and recruitment of BAT. The anti-obesity effect of some other food ingredients including tea catechins may also be attributable to the activation of the TRP-BAT axis. Thus, BAT is a promising target for combating obesity and related metabolic disorders in humans.

Assessment of human brown adipose tissue density during daily ingestion of thermogenic capsinoids using near-infrared time-resolved spectroscopy.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDGPET/CT) is widely used as a standard method for evaluating human brown adipose tissue (BAT), a recognized therapeutic target of obesity. However, a longitudinal BAT study using FDG-PET/CT is lacking owing to limitations of the method. Near-infrared time-resolved spectroscopy (NIR(TRS)) is a technique for evaluating human BAT density noninvasively. This study aimed to test whether NIRTRS could detect changes in BAT density during or after long-term intervention. First, using FDG-PET/CT, we confirmed a significant increase (+48.8%, P < 0.05) in BAT activity in the supraclavicular region after 6-week treatment with thermogenic capsaicin analogs, capsinoids. Next, 20 volunteers were administered either capsinoids or placebo daily for 8 weeks in a double-blind design, and BAT density was measured using NIR(TRS) every 2 weeks during the 8-week treatment period and an 8-week period after stopping treatment. Consistent with FDG-PET/CT results, NIR(TRS) successfully detected an increase in BAT density during the 8-week treatment (+46.4%, P < 0.05), and a decrease in the 8-week follow-up period (-12.5%, P = 0.07), only in the capsinoid-treated, but not the placebo, group. Thus, NIR(TRS) can be applied for quantitative assessment of BAT in longitudinal intervention studies in humans.

Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans.

Brown adipose tissue (BAT) contributes to whole-body energy expenditure (EE), especially cold-induced thermogenesis (CIT), in humans. Although it is known that EE and CIT vary seasonally, their relationship with BAT has not been investigated. In the present study, we examined the impact of BAT on seasonal variations of EE/CIT and thermal responses to cold exposure in a randomized crossover design. Forty-five healthy male volunteers participated, and their BAT was assessed by positron emission tomography and computed tomography. CIT, the difference of EE at 27ºC and after 2-h cold exposure at 19ºC, significantly increased in winter compared to summer, being greater in subjects with metabolically active BAT (High BAT, 185.6 kcal/d, 18.3 kcal/d, P<0.001) than those without (Low BAT, 90.6 kcal/d, -46.5 kcal/d, P<0.05). Multivariate regression analysis revealed a significant interaction effect between season and BAT on CIT (P<0.001). The cold-induced drop of tympanic temperature (Tty) and skin temperature (Tskin) in the forehead region and in the supraclavicular region close to BAT deposits were smaller in the High BAT group than in the Low BAT group in winter but not in summer. In contrast, the drop of Tskinin the subclavicular and peripheral regions distant from BAT was similar in the two groups in both seasons. In conclusion, CIT increased from summer to winter in a BAT-dependent manner, paralleling cold-induced changes in Tty/Tskin, indicating a role of BAT in seasonal changes in the thermogenic and thermal responses to cold exposure in humans.

Evaluation of Brown Adipose Tissue Using Near-Infrared Time-Resolved Spectroscopy.

Human brown adipose tissue (BAT) activity (SUVmax) has been typically evaluated by 18F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT). In this study, the objective was to detect human BAT by near-infrared time-resolved spectroscopy (NIRTRS), a noninvasive and simple method for measuring total hemoglobin concentration [total-Hb] and reduced scattering coefficient (µs') in the tissue. The [total-Hb] in the supraclavicular region of the BAT (+) (SUVmax≥2.0) group was 95.0±28.2 µM (mean+/-SD), which was significantly higher than that of the BAT (-) (SUVmax<2.0) group (52.0±14.8 µM), but not in other regions apart from the BAT deposits. The µs' in the supraclavicular region of the BAT (+) group was 8.4±1.7 cm(-1), which was significantly higher than that of BAT (-) group (4.3±1.0 cm(-1)), but not in other regions. The area under the receiver operating characteristic curve closest to (0, 1) for [total-Hb] and µs' to discriminate BAT (+) from BAT (-) was 72.5 µM and 6.3 cm(-1), respectively. The sensitivity, specificity, and accuracy for both parameters were 87.5, 100, and 93.3%, respectively. Our novel NIRTRS method is noninvasive, simple, and inexpensive compared with FDG-PET/CT, and is reliable for detecting human BAT.