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      Supraclavicular Skin Temperature as a Measure of 18F-FDG Uptake by BAT in Human Subjects

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          Abstract

          Background

          Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current ‘gold standard’ for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans.

          Subjects/Methods

          BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations.

          Results

          Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R 2 = 0.28, P = 0.010) and clavicular BAT volume (R 2 = 0.20, P = 0.030) and clavicular SUV max (R 2 = 0.27, P = 0.010), while core body temperature did not.

          Conclusions

          Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects.

          Trial Registration

          NTR 2473

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          Most cited references13

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          Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

          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.
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            Different metabolic responses of human brown adipose tissue to activation by cold and insulin.

            We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Nonshivering thermogenesis and its adequate measurement in metabolic studies.

              Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                12 June 2014
                : 9
                : 6
                : e98822
                Affiliations
                [1 ]Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
                [2 ]Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
                [3 ]Department of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands
                [4 ]Department of Nuclear Medicine, Rijnland Hospital, Leiderdorp, The Netherlands
                [5 ]Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
                [6 ]Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
                St. Joseph's Hospital and Medical Center, United States of America
                Author notes

                Competing Interests: This study was funded in part by Roba Metals B. V. IJsselstein and FMH Medical. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: MRB LEHB WvML IMJ PCNR. Performed the experiments: MRB LEHB RADvdL LPA-B FS. Analyzed the data: MRB LEHB RADvdL HJV. Wrote the paper: MRB LEHB RADvdL LPA-B FM HJV WDvML IMJ PCNR.

                Article
                PONE-D-14-06900
                10.1371/journal.pone.0098822
                4055666
                24922545
                509021f1-c775-4ea1-904d-9bb7d2309b75
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 February 2014
                : 7 May 2014
                Page count
                Pages: 8
                Funding
                This work was financed by the Dutch Diabetes Research Foundation (grant 2012.11.1500 to P. C. N. R. and M. R. B.). M. R. B. is supported by the Board of Directors of the Leiden University Medical Center (LUMC) and P. C. N. R. is Established Investigator of the Netherlands Heart Foundation (grant 2009T038). The authors also thank Roba Metals B. V. IJsselstein (Utrecht, The Netherlands) for financial support. The Blanketrol ® III cooling device was kindly provided by FMH Medical (Veenendaal, The Netherlands). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All funders, including Roba Metals B.V. IJsselstein and FHM Medical, do not have competing interests that interfere with, or could be perceived as interfering with, the complete and objective presentation, peer review, editorial decision-making, or publication of a manuscript. Furthermore, the financial support of these funders does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
                Categories
                Research Article
                Biology and Life Sciences
                Nutrition
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Tomography
                Positron Emission Tomography
                Endocrinology
                Diabetic Endocrinology
                Metabolic Disorders
                Diabetes Mellitus
                Type 2 Diabetes
                Radiology and Imaging

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                Uncategorized

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