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      The dark side of browning

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          Abstract

          The induction of brown-like adipocyte development in white adipose tissue (WAT) confers numerous metabolic benefits by decreasing adiposity and increasing energy expenditure. Therefore, WAT browning has gained considerable attention for its potential to reverse obesity and its associated co-morbidities. However, this perspective has been tainted by recent studies identifying the detrimental effects of inducing WAT browning. This review aims to highlight the adverse outcomes of both overactive and underactive browning activity, the harmful side effects of browning agents, as well as the molecular brake-switch system that has been proposed to regulate this process. Developing novel strategies that both sustain the metabolic improvements of WAT browning and attenuate the related adverse side effects is therefore essential for unlocking the therapeutic potential of browning agents in the treatment of metabolic diseases.

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          Thyroid hormone regulation of metabolism.

          Rashmi S Mullur, Yan-Yun Liu, Gregory A Brent (2014)
          Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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            Cancer cachexia: mediators, signaling, and metabolic pathways.

            Kenneth C.H. Fearon, David J. Glass, Denis C. Guttridge (2012)
            Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Developmental origin of fat: tracking obesity to its source.

              Stephane Gesta, Yu-Hua Tseng, C Kahn (2007)
              The development of obesity not only depends on the balance between food intake and caloric utilization but also on the balance between white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specialized for energy expenditure. In addition, some sites of white fat storage in the body are more closely linked than others to the metabolic complications of obesity, such as diabetes. In this Review, we consider how the developmental origins of fat contribute to its physiological, cellular, and molecular heterogeneity and explore how these factors may play a role in the growing epidemic of obesity.
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                Author and article information

                Contributors
                Li Qiang:
                ORCID: http://orcid.org/0000-0001-8322-1797
                lq2123@cumc.columbia.edu
                Journal
                Journal ID (nlm-ta): Protein Cell
                Journal ID (iso-abbrev): Protein Cell
                Title: Protein & Cell
                Publisher: Higher Education Press (Beijing )
                ISSN (Print): 1674-800X
                ISSN (Electronic): 1674-8018
                Publication date (Electronic): 4 July 2017
                Publication date PMC-release: 4 July 2017
                Publication date (Print): February 2018
                Volume: 9
                Issue: 2
                Pages: 152-163
                Affiliations
                [1 ]ISNI 0000000419368729, GRID grid.21729.3f, Institute of Human Nutrition, College of Physicians and Surgeons, , Columbia University, ; New York, NY 10032 USA
                [2 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, , Columbia University, ; New York, NY 10032 USA
                Author information
                http://orcid.org/0000-0001-8322-1797
                Article
                Publisher ID: 434
                DOI: 10.1007/s13238-017-0434-2
                PMC ID: 5818365
                PubMed ID: 28677104
                SO-VID: c7338ba3-cb41-495f-8777-a7d99610cf0d
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.

                History
                Date received : 2 April 2017
                Date accepted : 31 May 2017
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © HEP and Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Keywords: adipocyte,browning,beige adipocyte,thermogenesis,obesity,diabetes
                Data availability:
                Keywords: adipocyte, browning, beige adipocyte, thermogenesis, obesity, diabetes

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