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      Mapping of human brown adipose tissue in lean and obese young men

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          Significance

          Brown adipose tissue (BAT) is currently being explored as a target for the treatment of obesity and diabetes after repeated demonstrations on positron emission tomography-computed tomography (PET/CT) imaging of its ability to metabolize glucose following acute cold exposure. Measurement of whole-body BAT volume, activity, and distribution is difficult because brown adipocytes are structurally commingled among white adipose tissue, muscle, and blood vessels. Thus, BAT’s potential contribution to metabolism remains unclear. To address this, we have identified several refinements to improve current PET/CT analyses and demonstrated their impact in healthy lean vs. obese individuals. Using the refined technique, we defined whole-body BAT distribution and estimated its metabolic capacity and found that it is substantially higher than usually reported.

          Abstract

          Human brown adipose tissue (BAT) can be activated to increase glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. Data on the functional and anatomic characteristics of BAT are limited, however. In 20 healthy young men [12 lean, mean body mass index (BMI) 23.2 ± 1.9 kg/m 2; 8 obese, BMI 34.8 ± 3.3 kg/m 2] after 5 h of tolerable cold exposure, we measured BAT volume and activity by 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.1–71%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT—cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal—with 67 ± 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential.

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          Most cited references21

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          From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors.

          The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with (18)F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment. Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to (18)F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test-retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm(3) in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for "response," and deferring to RECIST 1.1 in cases that do not have (18)F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas (18)F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.
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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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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                8 August 2017
                24 July 2017
                24 July 2017
                : 114
                : 32
                : 8649-8654
                Affiliations
                [1] aDiabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892;
                [2] bDepartment of Endocrinology and Metabolism, Huashan Hospital, Fudan University , Shanghai, 200032, China;
                [3] cDivision of Nuclear Medicine and Molecular Imaging, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215;
                [4] dDepartment of Positron Emission Tomography, National Institutes of Health , Bethesda, MD 20892;
                [5] e Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892
                Author notes
                3To whom correspondence should be addressed. Email: chenkong@ 123456niddk.nih.gov .

                Edited by Stephen O’Rahilly, University of Cambridge, Cambridge, United Kingdom, and approved June 7, 2017 (received for review March 30, 2017)

                Author contributions: R.J.B. and K.Y.C. designed research; B.P.L., S.H., R.J.B., C.J.D., A.S.B., S.M., W.D., G.G., K.P., P.H., and K.Y.C. performed research; I.T., W.D., G.M.K., P.H., and K.Y.C. contributed new reagents/analytic tools; B.P.L., S.H., R.J.B., I.T., A.M.C., and K.Y.C. analyzed data; and B.P.L., S.H., R.J.B., W.D., A.M.C., and K.Y.C. wrote the paper.

                1B.P.L. and S.H. contributed equally to this work.

                2A.M.C. and K.Y.C. contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-5570-9346
                http://orcid.org/0000-0002-0306-1904
                Article
                PMC5559032 PMC5559032 5559032 201705287
                10.1073/pnas.1705287114
                5559032
                28739898
                502fbdd4-26af-4f20-b731-bce36d25964f

                Freely available online through the PNAS open access option.

                History
                Page count
                Pages: 6
                Funding
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: Z01 DK071014
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: Z01 DK075116
                Categories
                Biological Sciences
                Physiology

                brown fat,PET/CT,obesity,metabolism
                brown fat, PET/CT, obesity, metabolism

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