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Saeki K.,National Health Research Institute | Nishio M.,National Health Research Institute | Yoneshiro T.,Hokkaido University | Nakahara M.,National Health Research Institute | And 10 more authors.
Cell Metabolism | Year: 2012

Brown adipose tissue is attracting much attention due to its antiobestic effects; however, its development and involvement in metabolic improvement remain elusive. Here we established a method for a high-efficiency (>90%) differentiation of human pluripotent stem cells (hPSCs) into functional classical brown adipocytes (BAs) using specific hemopoietin cocktail (HC) without exogenous gene transfer. BAs were not generated without HC, and lack of a component of HC induced white adipocyte (WA) marker expressions. hPSC-derived BA (hPSCdBA) showed respiratory and thermogenic activation by β-adrenergic receptor (AdrRβ) stimuli and augmented lipid and glucose tolerance, whereas human multipotent stromal cell-derived WA (hMSCdWA) improved lipid but inhibited glucose metabolism. Cotransplantation of hPSCdBA normalized hMSCdWA-induced glucose intolerance. Surprisingly, hPSCdBAs expressed various hemopoietin genes, serving as stroma for myeloid progenitors. Moreover, AdrRβ stimuli enhanced recovery from chemotherapy-induced myelosuppression. Our study enhances our understanding of BA, identifying roles in metabolic and hemogenic regulation. © 2012 Elsevier Inc.


PubMed | Ajinomoto Co., LSI Sapporo Clinic, National School of Sport, Daito Bunka University and 4 more.
Type: Journal Article | Journal: Journal of biomedical optics | Year: 2016

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.


Matsushita M.,Tenshi College | Yoneshiro T.,Hokkaido University | Aita S.,Hakodate Junior College | Kameya T.,LSI Sapporo Clinic | And 2 more authors.
International Journal of Obesity | Year: 2014

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. © 2014 Macmillan Publishers Limited All rights reserved.


Yoneshiro T.,Hokkaido University | Ogawa T.,Wakunaga Pharmaceutical Co. | Okamoto N.,Wakunaga Pharmaceutical Co. | Matsushita M.,Tenshi College | And 6 more authors.
International Journal of Obesity | Year: 2013

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. © 2013 Macmillan Publishers Limited.


Nirengi S.,Ritsumeikan University | Yoneshiro T.,Hokkaido University | Sugie H.,LSI Sapporo Clinic | Saito M.,Hokkaido University | Hamaoka T.,Ritsumeikan University
Obesity | Year: 2015

Objective Human brown adipose tissue (BAT) activity has been typically evaluated by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT). However, FDG-PET/CT has serious limitations (e.g., radiation and cold exposure). This study evaluated BAT density using near-infrared time-resolved spectroscopy (NIRTRS), a simple and noninvasive method of measuring the indices of tissue hemoglobin concentration [total-Hb] and mitochondrial density (μs-). Methods The NIRTRS parameters at 760, 800, and 830 nm in the supraclavicular region potentially containing BAT were evaluated. First, the NIRTRS parameters were compared at 27°C and during a 2-h cold exposure (19°C) in 18 men. Then, NIRTRS parameters at 27°C were compared with mean standardized uptake values (SUVmean) assessed by FDG-PET/CT after the 2-h cold exposure (19°C) in 29 men. Results There was no significant difference between the NIRTRS parameters at 27°C and 19°C. The [total-Hb] and μs- were significantly correlated to SUVmean (r-=-0.73 and r-=-0.64, respectively). A receiver operating characteristic analysis revealed that the sensitivity (75.0-82.4%), specificity (91.7-100%), and accuracy (82.8-86.2%) of the NIRTRS parameters were all good to determine the NIRTRS reliability. Conclusions Our novel NIRTRS method is noninvasive and simple and can reliably assess human BAT density in the supraclavicular region. © 2014 The Obesity Society.


Yoneshiro T.,Hokkaido University | Aita S.,Tenshi College | Matsushita M.,Tenshi College | Kayahara T.,Ajinomoto Co. | And 4 more authors.
Journal of Clinical Investigation | Year: 2013

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 19C 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 17C 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.


Yoneshiro T.,Tenshi College | Aita S.,Tenshi College | Matsushita M.,Tenshi College | Okamatsu-Ogura Y.,Hokkaido University | And 5 more authors.
Obesity | Year: 2011

Brown adipose tissue (BAT) can be identified by 18 F-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. © 2011 The Obesity Society.


Sugita J.,Tenshi College | Sugita J.,Kanebo Cosmetics Inc. | Yoneshiro T.,Hokkaido University | Hatano T.,Tenshi College | And 7 more authors.
British Journal of Nutrition | Year: 2013

Brown adipose tissue (BAT) is responsible for cold-and diet-induced thermogenesis, and thereby contributes to the control of whole-body energy expenditure (EE) and body fat content. BAT activity can be assessed by fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in human subjects. Grains of paradise (GP, Aframomum melegueta), a species of the ginger family, contain pungent, aromatic ketones such as 6-paradol, 6-gingerol and 6-shogaol. An alcohol extract of GP seeds and 6-paradol are known to activate BAT thermogenesis in small rodents. The present study aimed to examine the effects of the GP extract on whole-body EE and to analyse its relation to BAT activity in men. A total of nineteen healthy male volunteers aged 20-32 years underwent FDG-PET after 2 h of exposure to cold at 19°C with light clothing. A total of twelve subjects showed marked FDG uptake into the adipose tissue of the supraclavicular and paraspinal regions (BAT positive). The remaining seven showed no detectable uptake (BAT negative). Within 4 weeks after the FDG-PET examination, whole-body EE was measured at 27°C before and after oral ingestion of GP extract (40 mg) in a single-blind, randomised, placebo-controlled, crossover design. The resting EE of the BAT-positive group did not differ from that of the BAT-negative group. After GP extract ingestion, the EE of the BAT-positive group increased within 2 h to a significantly greater (P< 0·01) level than that of the BAT-negative group. Placebo ingestion produced no significant change in EE. These results suggest that oral ingestion of GP extract increases whole-body EE through the activation of BAT in human subjects. © 2012 The Authors.


Yoneshiro T.,Hokkaido University | Aita S.,Tenshi College | Kawai Y.,LSI Sapporo Clinic | Iwanaga T.,Hokkaido University | Saito M.,Tenshi College
American Journal of Clinical Nutrition | Year: 2012

Background: Capsinoids - nonpungent capsaicin analogs - are known to activate brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in small rodents. BAT activity can be assessed by [ 18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) in humans. Objectives: The aims of the current study were to examine the acute effects of capsinoid ingestion on EE and to analyze its relation to BAT activity in humans. Design: Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature, after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover design. Results: When exposed to cold, 10 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT-positive group), whereas the remaining 8 subjects (BAT-negative group) showed no detectable uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226 kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group (NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7 ± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P < 0.01). Placebo ingestion produced no significant change in either group. Neither capsinoids nor placebo changed the skin temperature in various regions, including regions close to BAT deposits. Conclusion: Capsinoid ingestion increases EE through the activation of BAT in humans. This trial was registered at http://www.umin.ac.jp/ctr/ as UMIN 000006073. © 2012 American Society for Nutrition.


Yoneshiro T.,Tenshi College | Aita S.,Tenshi College | Matsushita M.,Tenshi College | Kameya T.,LSI Sapporo Clinic | And 3 more authors.
Obesity | Year: 2011

Brown adipose tissue (BAT) can be identified by 18 F-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 97kcal/day, being comparable with that of the BAT-negative group (1,434 246kcal/day). After cold exposure, the energy expenditure increased markedly by 410 293 (P 0.05) and slightly by 42 114kcal/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. © 2010 The Obesity Society.

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