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      Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute Cold-Induced Brown Adipose Tissue Activation

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          Abstract

          Background

          Adipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.

          Objective

          Our study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.

          Design

          Nineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose ( 18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.

          Main Outcome Measures

          Plasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).

          Results

          Plasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P  = 0.03), and inversely correlated with MR sFF (coefficient, −404; P  = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.

          Conclusion

          Higher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.

          Highlights

          A higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.

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          Most cited references35

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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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            Adiponectin acts in the brain to decrease body weight.

            Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.
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              Impact of Age on the Relationships of Brown Adipose Tissue With Sex and Adiposity in Humans

              OBJECTIVE Brown adipose tissue (BAT) regulates energy homeostasis and fat mass in mammals and newborns and, most likely, in adult humans. Because BAT activity and BAT mass decline with age in humans, the impact of BAT on adiposity may decrease with aging. In the present study we addressed this hypothesis and further investigated the effect of age on the sex differences in BAT activity and BAT mass. RESEARCH DESIGN AND METHODS Data from 260 subjects (98 with BAT and 162 study date–matched control subjects) who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) under thermoneutral conditions were analyzed. BAT activity and BAT mass were determined in the upper body. RESULTS BAT activity and BAT mass were higher in female (1.59 ± 0.10 and 32 ± 5 g vs. 1.02 ± 0.10 and 18 ± 4 g, both P ≤ 0.0006) than in male subjects. In multivariate analyses, sex (P < 0.0001), age (P < 0.0001), and BMI (P = 0.0018) were associated independently with BAT activity. Interestingly, only in male subjects was there an interaction between BMI and age in determining BAT activity (P = 0.008) and BAT mass (P = 0.0002); BMI decreased with increasing BAT activity and BAT mass in the lowest age tertile (Spearman rank correlation coefficient r s = −0.38, P = 0.015 and rs = −0.37, P = 0.017, respectively), not in the higher age tertiles. Furthermore, BAT activity and mass differed between female and male subjects only in the upper two age tertiles (all P ≤ 0.09). CONCLUSIONS Our data corroborate that, in general, BAT activity and BAT mass are elevated in female subjects and in younger people. Importantly, we provide novel evidence that the impact of BAT activity and BAT mass on adiposity appears to decline with aging only in male subjects. Furthermore, while BAT activity and BAT mass only moderately decline with increasing age in female subjects, a much stronger effect is found in male subjects.
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                Author and article information

                Journal
                J Clin Endocrinol Metab
                J. Clin. Endocrinol. Metab
                jcem
                The Journal of Clinical Endocrinology and Metabolism
                Oxford University Press (US )
                0021-972X
                1945-7197
                March 2020
                08 January 2020
                08 January 2020
                : 105
                : 3
                : dgaa005
                Affiliations
                [1 ] Clinical Nutrition Research Centre, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR) and National University Health System (NUHS) , Singapore
                [2 ] Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences , Shanghai, China
                [3 ] Department of Nuclear Medicine, First Hospital of Shanxi Medical University , Taiyuan, Shanxi, China
                [4 ] Molecular Imaging Precision Medicine Collaborative Innovation Centre, Shanxi Medical University , Taiyuan, China
                [5 ] Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR) , Singapore
                [6 ] Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR) , Singapore
                [7 ] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS) , Singapore
                [8 ] Departments of Physiology & Medicine, National University of Singapore (NUS) , Singapore
                [9 ] Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School , Singapore
                [10 ] Lee Kong Chian School of Medicine, Nanyang Technological University (NTU) , Singapore
                [11 ] Department of Endocrinology, Tan Tock Seng Hospital (TTSH) , Singapore
                Author notes
                Correspondence and Reprint Requests: Melvin Khee-Shing Leow, MD, PhD, FACP, FACE (USA), FRCP (Edin), FRCPath, Centre for Translational Medicine, 14 Medical Drive #07-02, MD 6 Building, Yong Loo Lin School of Medicine, Singapore, Singapore 117599. Email: melvin_leow@ 123456sics.a-star.edu.sg .

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-7650-3400
                Article
                dgaa005
                10.1210/clinem/dgaa005
                7015460
                31912874
                c4c9533d-a7b2-43cc-a6f5-e2cf7dc211d9
                © Endocrine Society 2020.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 07 October 2019
                : 07 January 2020
                : 12 February 2020
                Page count
                Pages: 12
                Funding
                Funded by: National Medical Research Council 10.13039/501100001349
                Award ID: NMRC/CSA-INV/0003/2015
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81671775
                Categories
                Clinical Research Article

                Endocrinology & Diabetes
                cold-induced supraclavicular bat activity,adiponectin,fgf21,leptin,tnfα
                Endocrinology & Diabetes
                cold-induced supraclavicular bat activity, adiponectin, fgf21, leptin, tnfα

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