Mami Matsushita

High Incidence of Metabolically Active Brown Adipose Tissue in Healthy Adult Humans: Effects of Cold Exposure and Adiposity

OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[18F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23–65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19°C) for 2 h, 17 of 32 younger subjects (aged 23–35 years) and 2 of 24 elderly subjects (aged 38–65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27°C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.

Recruited brown adipose tissue as an antiobesity agent in humans

Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.

Brown Adipose Tissue, Whole‐Body Energy Expenditure, and Thermogenesis in Healthy Adult Men

Brown adipose tissue (BAT) can be identified by 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) in adult humans. Thirteen healthy male volunteers aged 20–28 years underwent FDG‐PET after 2‐h cold exposure at 19 °C with light‐clothing and intermittently putting their legs on an ice block. When exposed to cold, 6 out of the 13 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT‐positive group), whereas the remaining seven showed no detectable uptake (BAT‐negative group). The BMI and body fat content were similar in the two groups. Under warm conditions at 27 °C, the energy expenditure of the BAT‐positive group estimated by indirect calorimetry was 1,446 ± 97 kcal/day, being comparable with that of the BAT‐negative group (1,434 ± 246 kcal/day). After cold exposure, the energy expenditure increased markedly by 410 ± 293 (P < 0.05) and slightly by 42 ± 114 kcal/day (P = 0.37) in the BAT‐positive and ‐negative groups, respectively. A positive correlation (P < 0.05) was found between the cold‐induced rise in energy expenditure and the BAT activity quantified from FDG uptake. After cold exposure, the skin temperature in the supraclavicular region close to BAT deposits dropped by 0.14 °C in the BAT‐positive group, whereas it dropped more markedly (P < 0.01) by 0.60 °C in the BAT‐negative group. The skin temperature drop in other regions apart from BAT deposits was similar in the two groups. These results suggest that BAT is involved in cold‐induced increases in whole‐body energy expenditure, and, thereby, the control of body temperature and adiposity in adult humans.

Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.

Brown adipose tissue (BAT) can be identified by 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) combined with X‐ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty‐two healthy volunteers aged 20–73 years (103 males and 59 females) underwent FDG‐PET/CT after 2‐h cold exposure at 19 °C with light clothing. Cold‐activated BAT was detected in 41% of the subjects (BAT‐positive). Compared with the BAT‐negative group, the BAT‐positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold‐activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity‐related parameters showed some sex differences, but increased with age in the BAT‐negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT‐positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.

Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans

Background:Brown adipose tissue (BAT) is involved in the regulation of whole-body energy expenditure and adiposity. Some clinical studies have reported an association between BAT and blood glucose in humans.Objective:To examine the impact of BAT on glucose metabolism, independent of that of body fatness, age and sex in healthy adult humans.Methods:Two hundred and sixty healthy volunteers (184 males and 76 females, 20–72 years old) underwent fluorodeoxyglucose-positron emission tomography and computed tomography after 2 h of cold exposure to assess maximal BAT activity. Blood parameters including glucose, HbA1c and low-density lipoprotein (LDL)/high-density lipoprotein-cholesterol were measured by conventional methods, and body fatness was estimated from body mass index (BMI), body fat mass and abdominal fat area. The impact of BAT on body fatness and blood parameters was determined by logistic regression with the use of univariate and multivariate models.Results:Cold-activated BAT was detected in 125 (48%) out of 260 subjects. When compared with subjects without detectable BAT, those with detectable BAT were younger and showed lower adiposity-related parameters such as the BMI, body fat mass and abdominal fat area. Although blood parameters were within the normal range in the two subject groups, HbA1c, total cholesterol and LDL-cholesterol were significantly lower in the BAT-positive group. Blood glucose also tended to be lower in the BAT-positive group. Logistic regression demonstrated that BAT, in addition to age and sex, was independently associated with BMI, body fat mass, and abdominal visceral and subcutaneous fat areas. For blood parameters, multivariate analysis after adjustment for age, sex and body fatness revealed that BAT was a significantly independent determinant of glucose and HbA1c.Conclusion:BAT, independent of age, sex and body fatness, has a significant impact on glucose metabolism in adult healthy humans.

Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans

Background:Brown adipose tissue (BAT) is involved in the regulation of whole-body energy expenditure and adiposity. The activity and prevalence of BAT decrease with age in humans.Objective:To examine the effects of single nucleotide polymorphisms of the genes for uncoupling protein 1 (UCP1) and β3-adrenergic receptor (β3AR), key molecules of BAT thermogenesis, on age-related decline of BAT activity and accumulation of body fat in humans.Methods:One hundred ninety-nine healthy volunteers (20–72 years old (y.o.)) underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) after 2-h cold exposure to assess BAT activity. The visceral and subcutaneous fat areas at the abdominal level were estimated from the CT images. They were genotyped for −3826 A/G polymorphism of the UCP1 gene and 64 Trp/Arg mutation of the β3AR gene.Results:BAT was detected in 88 subjects out of 199 (44%), more in younger (⩽30 y.o., 55%) than older subjects (>40 y.o., 15%). BAT prevalence of older subjects tended to be lower in the UCP1 G/G group than the A allele group (A/A and A/G), and also in the β3AR Arg allele group (Trp/Arg and Arg/Arg) than the Trp/Trp group. When compared subjects who had two or more base substitutions on the two genes (the 2–4 allele group) with those who had less than two base substitutions (the 0–1 allele group), BAT prevalence was comparable in younger subjects (62% vs 50%) but lower in older subjects (0% vs 24%, P<0.05). Visceral fat area of the 2–4 allele group was higher than that of the 0–1 allele group (P<0.05) in older subjects, but not in younger subjects.Conclusion:UCP1 −3826 A/G and β3AR 64 Trp/Arg substitutions accelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age.

Food Ingredients as Anti-Obesity Agents

Brown adipose tissue (BAT) is a site of adaptive non-shivering thermogenesis after cold exposure, and is involved in the regulation of energy expenditure and body fatness. BAT can be activated and recruited by not only cold exposure but also by various food ingredients including capsaicin in chili pepper and catechins in green tea, which would be easily and safely applicable to our daily life for preventing obesity.

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

Abstract. F18-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/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 (NIRTRS) 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 NIRTRS every 2 weeks during the 8-week treatment period and an 8-week period after stopping treatment. Consistent with FDG-PET/CT results, NIRTRS 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, NIRTRS 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.