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      Caffeine exposure induces browning features in adipose tissue in vitro and in vivo

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          Abstract

          Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans.

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          Most cited references 54

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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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            Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation.

            Mitochondria play an essential role in the ability of brown fat to generate heat, and the PGC-1 coactivators control several aspects of mitochondrial biogenesis. To investigate their specific roles in brown fat cells, we generated immortal preadipocyte lines from the brown adipose tissue of mice lacking PGC-1alpha. We could then efficiently knockdown PGC-1beta expression by shRNA expression. Loss of PGC-1alpha did not alter brown fat differentiation but severely reduced the induction of thermogenic genes. Cells deficient in either PGC-1alpha or PGC-1beta coactivators showed a small decrease in the differentiation-dependant program of mitochondrial biogenesis and respiration; however, this increase in mitochondrial number and function was totally abolished during brown fat differentiation when both PGC-1alpha and PGC-1beta were deficient. These data show that PGC-1alpha is essential for brown fat thermogenesis but not brown fat differentiation, and the PGC-1 coactivators play an absolutely essential but complementary function in differentiation-induced mitochondrial biogenesis.
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              TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis.

              PGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                michael.symonds@nottingham.ac.uk
                virginie.sottile@nottingham.ac.uk
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 June 2019
                24 June 2019
                2019
                : 9
                Affiliations
                [1 ]ISNI 0000 0004 1936 8868, GRID grid.4563.4, Wolfson Centre for Stem Cells, Tissue Engineering and Modelling (STEM), Division of Cancer & Stem Cells, , University of Nottingham, ; Nottingham, NG7 2UH United Kingdom
                [2 ]ISNI 0000 0004 1936 8868, GRID grid.4563.4, The Early Life Research Unit, Division of Child Health, Obstetrics and Gynaecology, , University of Nottingham, ; Nottingham, NG7 2UH United Kingdom
                [3 ]ISNI 0000 0004 1936 8868, GRID grid.4563.4, Nottingham Digestive Disease Centre and Biomedical Research Centre School of Medicine, , University of Nottingham, ; Nottingham, NG7 2UH United Kingdom
                [4 ]ISNI 0000 0004 1936 8868, GRID grid.4563.4, Department of Electrical and Electronic Engineering, Faculty of Engineering, , University of Nottingham, ; Nottingham, NG7 2RD United Kingdom
                [5 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, VA Endocrinology and Diabetes Division, VA Greater Los Angeles Healthcare System, and Department of Medicine, , David Geffen School of Medicine; University of California, ; Los Angeles, CA 90073 USA
                Article
                45540
                10.1038/s41598-019-45540-1
                6591281
                31235722
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000268, RCUK | Biotechnology and Biological Sciences Research Council (BBSRC);
                Categories
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                © The Author(s) 2019

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                molecular imaging, stem-cell research

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