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Brown Adipose Tissue Is Involved in Diet-Induced Thermogenesis and Whole-Body Fat Utilization in Healthy Humans

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Brown Adipose Tissue Is Involved in Diet-Induced Thermogenesis and Whole-Body Fat Utilization in Healthy Humans OPEN International Journal of Obesity (2016) 40, 1655–1661 www.nature.com/ijo ORIGINAL ARTICLE Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans M Hibi1, S Oishi1, M Matsushita2, T Yoneshiro3, T Yamaguchi1, C Usui4, K Yasunaga1, Y Katsuragi1, K Kubota5, S Tanaka4 and M Saito2 BACKGROUND/OBJECTIVES: Brown adipose tissue (BAT) is a potential therapeutic target against obesity and diabetes through thermogenesis and substrate disposal with cold exposure. The role of BAT in energy metabolism under thermoneutral conditions, however, remains controversial. We assessed the contribution of BAT to energy expenditure (EE), particularly diet-induced thermogenesis (DIT), and substrate utilization in human adults. 18 METHODS: In this cross-sectional study, BAT activity was evaluated in 21 men using F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) after cold exposure (19 °C). The subjects were divided into BAT-positive (n=13) and BAT-negative (n=8) groups according to the 18F-FDG-PET/CT findings. Twenty-four hour EE, DIT and respiratory quotient were measured using a whole-room indirect calorimeter at 27 °C. RESULTS: Body composition, blood metabolites and 24-h EE did not differ between groups. DIT (%), calculated as DIT divided by total energy intake, however, was significantly higher in the BAT-positive group (BAT-positive: 9.7 ± 2.5%, BAT-negative: 6.5 ± 4.0%, P = 0.03). The 24-h respiratory quotient was significantly lower (P = 0.03) in the BAT-positive group (0.861 ± 0.027) than in the BAT- negative group (0.889 ± 0.024). CONCLUSION: DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism. International Journal of Obesity (2016) 40, 1655–1661; doi:10.1038/ijo.2016.124 INTRODUCTION BAT contains uncoupling protein 1 (UCP1), which mediates Brown adipose tissue (BAT) is an important regulatory tissue for the uncoupling of mitochondrial substrate oxidation from core body temperature and whole-body energy expenditure (EE) ATP production, leading to the release of energy as heat from 1 in small rodents and human infants.1 Recent human studies using free fatty acid oxidation. Activation of BAT is dependent on UCP1 18F-fluoro-2-deoxy- -glucose-positron emission tomography in expression and the sympathetic nervous system (SNS) through D β 11 combination with computed tomography (18F-FDG-PET/CT) 3-adrenoreceptors. The SNS is stimulated by cold, diet, stress – fl revealed that adult humans also have active BAT.2 5 Based on and in ammation, which leads to increases in obligatory and/or several cross-sectional studies, human BAT decreases with age facultative thermogenesis and may explain how BAT contributes to adaptive thermogenesis, including diet-induced thermogenesis and is inversely correlated with body mass index or visceral fat 11,12 – (DIT) and CIT. The role of BAT in DIT in adult humans is not area.2,3,6 8 The age-dependent decrease in BAT might be clear, but a polymorphism in UCP1 (-3826A/G) is associated with associated with an accumulation of body weight and fat.6,8 lower postprandial EE.13 Moreover, UCP1 gene polymorphisms Active BAT has a protective role against obesity and diabetes also accelerate age-related decreases in BAT activity.14 Thus, through the regulation of cold-induced thermogenesis (CIT).9,10 BAT may have a specific role in postprandial thermogenesis to Yoneshiro et al.9 reported that CIT, evaluated based on the produce heat from fatty acid oxidation, but this has not yet been difference between resting EE at a thermoneutral temperature 15,16 17 demonstrated directly. More recently, Peterson et al. (27 °C) and EE at a non-shivering cold temperature (19 °C), examined the thermic response to a 50% overfeeding diet increases by up to 12% in subjects with metabolically active 10 following a 4-week cold intervention. Despite increases in CIT BAT. Chondronikola et al. also reported that prolonged cold and SNS activity, DIT was unchanged in response to 50% – exposure (5 8 h) with a liquid cooling vest (20 °C) increases resting overfeeding. On the other hand, Lee et al.18 demonstrated that EE, whole-body glucose disposal and insulin sensitivity in those BAT recruitment is accompanied by enhanced DIT and post- with active BAT. These findings suggest that BAT in adult humans prandial insulin sensitivity. Thus, the role of BAT in energy has a role in whole-body EE and substrate metabolism, at least metabolism in free-living humans remains controversial. under cold conditions. Such non-shivering cold exposure, In the present study, to clarify the relationship among however, is uncommon under free-living conditions in more BAT activity, EE and substrate utilization in humans, we compared temperate climates. Further investigation is required to clarify the 24-h EE, DIT and whole-body substrate oxidation under free-living contribution of BAT to whole-body EE and substrate utilization conditions between subjects with and without metabolically active under thermoneutral and free-living conditions. BAT using a whole-room indirect calorimeter. We hypothesized 1Health Care Food Research Laboratories, Kao Corporation, Tokyo, Japan; 2Department of Nutrition, Tenshi College, Sapporo, Japan; 3Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan; 4Department of Nutritional Science, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan and 5Division of Nuclear Medicine, Department of Radiology, National Center for Global Health and Medicine, Tokyo, Japan. Correspondence: Dr M Hibi, Health Care Food Research Laboratories, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo 131-8501, Japan. E-mail: [email protected] Received 12 April 2016; revised 6 June 2016; accepted 23 June 2016; accepted article preview online 19 July 2016; advance online publication, 9 August 2016 Brown fat in DIT and fat oxidation M Hibi et al 1656 that BAT-positive subjects would have higher DIT and substrate intake (EI) was individually adjusted from the basal metabolic rate utilization than BAT-negative subjects. (BMR) predicted using the formula by Ganpule et al.19 based on subject age, sex, height and body weight, and multiplied by 1.3 as the limited physical activity level. The three meals were identical and comprised SUBJECTS AND METHODS a rice bowl with grilled seafood and pork, tofu, and miso-soup without any spice, containing 15 energy percent protein, 25 energy percent Subjects fat and 60 energy percent carbohydrate (CHO). The energy composition Twenty-one healthy men were recruited through poster advertisements and amount of each of the three meals was exactly the same. Subjects and word of mouth. Inclusion criteria were as follows: 20–50 years of age went to bed at 0000 hours and got up at 0700 hours. The time from − 2 and a body mass index of 18.0–24.9 (kgm ). Participants were excluded if 0715 to 0900 hours was used for resting and a low-intensity activity they had a history of, or required, medication for cardiovascular disease, program (e.g., personal computer work, jigsaw puzzles and folding hypertension, diabetes, hypercholesterolemia, hyperglycemia, hyperlipide- laundry were performed for 20 min, respectively). For the remaining mia, eating disorders, smoking, excessive alcohol intake (430 g alcohol/d), time, the subjects were allowed free activity so as to maintain a situation allergies to ingredients in the test food, or worked as a shift worker or similar to free-living. Sleeping other than at the scheduled time was experienced a weight change of more than 2.0 kg during the 2 months not allowed. prior to the trial. The Institutional Review Boards of the National Institute of Health and Nutrition, Tenshi College, National Center for Global Health and Medicine, and Kao Corporation approved the study protocol. All subjects Whole-room indirect calorimeter provided written informed consent before study commencement. Twenty-four hour calorimetric measurements were performed using a whole-room indirect calorimeter (Fuji Medical Science Co. Ltd., Chiba, 20 18 Japan). Air in the chamber was pumped out at a rate of 100 L per min. F-FDG-PET/CT Temperature and relative humidity of the incoming fresh air were During the winter (between late December and early March) from 2013 to maintained at 27.0 ± 0.2 °C and 50.0 ± 3.0%, respectively. The air samples 18 2015 in Japan, BAT activity in the subjects was measured using F-FDG- were dried using a gas-sampling unit (CPF-8000, Shimadzu Corp., Kyoto, PET/CT. Subjects were assessed in the morning after fasting for 6–12 h. Japan) and analyzed using a mass spectrometer (VG PRIMA δB, Thermo The subjects wore light clothes (T-shirt and shorts) and remained in a room Fisher Scientific, Cheshire, UK), which was calibrated biweekly using adjusted to 19 °C for 2 h while intermittently placing a towel-wrapped ice standard gas. Oxygen consumption (VO2) and carbon dioxide production 18 – 21 block against the soles of their feet. After 1 h, F-FDG (1.66 5.18 MBq per (VCO2) were calculated using the formula of Henning et al. The VO2 and kg body weight) was administered intravenously and the subjects VCO2 data were offset by 2 min to adjust for the response lag time of the 2,6,8 remained in the same cold conditions for another hour. One hour respiratory measurements. VO2 and VCO2 were calculated over 30 min to 18 after the administration of F-FDG, a whole-body PET/CT scan was obtain the EE and respiratory quotient (RQ). Based on the 24-h VO2 and performed at 24 °C using a dedicated PET/CT system (either Aquiduo VCO2, as well as nitrogen excretion, total EE (TEE) and RQ were (Toshiba Medical Systems, Otawara, Japan), Biograph 16 (Siemens Medical calculated.22,23 Physical activity levels were monitored using an infrared Solutions, Knoxville, TN, USA), or Discovery PET/CT 600 (GE Healthcare, motion sensor (AMP2009B01, Matsushita Automation Controls Co.
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