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      The brain and brown fat

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          Abstract

          Brown adipose tissue (BAT) is a specialized organ responsible for thermogenesis, a process required for maintaining body temperature. BAT is regulated by the sympathetic nervous system (SNS), which activates lipolysis and mitochondrial uncoupling in brown adipocytes. For many years, BAT was considered to be important only in small mammals and newborn humans, but recent data have shown that BAT is also functional in adult humans. On the basis of this evidence, extensive research has been focused on BAT function, where new molecules, such as irisin and bone morphogenetic proteins, particularly BMP7 and BMP8B, as well as novel central factors and new regulatory mechanisms, such as orexins and the canonical ventomedial nucleus of the hypothalamus (VMH) AMP- activated protein kinase (AMPK)–SNS–BAT axis, have been discovered and emerged as potential drug targets to combat obesity. In this review we provide an overview of the complex central regulation of BAT and how different neuronal cell populations co-ordinately work to maintain energy homeostasis.

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          Most cited references273

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          The menthol receptor TRPM8 is the principal detector of environmental cold.

          Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 degrees C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 degrees C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.
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            A TRP channel that senses cold stimuli and menthol.

            A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the molecules that mediate thermoreception by these neurons. Vanilloid Receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here we describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temperature-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temperatures and by a cooling agent, menthol. Our identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.
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              Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.

              Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.
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                Author and article information

                Contributors
                Journal
                Ann Med
                Ann. Med
                sann
                Annals of Medicine
                Taylor & Francis
                0785-3890
                1365-2060
                March 2015
                10 June 2014
                : 47
                : 2
                : 150-168
                Affiliations
                [1 ]Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria , Santiago de Compostela, 15782, Spain
                [2 ]CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) , Santiago de Compostela, 15706, Spain
                [3 ]Department of Surgery, CIMUS, University of Santiago de Compostela-Instituto de Investigacion Sanitaria , Santiago de Compostela, 15782, Spain
                [4 ]Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela , Santiago de Compostela 15706, Spain
                [5 ]Department of Clinical Science, K.G. Jebsen Center for Diabetes Research, University of Bergen , Bergen, Norway
                [6 ]Department of Pharmacology, University of Iowa , Iowa City, IA 52242, USA
                [7 ]Department of Internal Medicine, University of Iowa , Iowa City, IA 52242, USA
                Author notes
                Correspondence: Cristina Contreras PhD., and Miguel López, PhD., Department of Physiology, NeurObesity Group, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria , Santiago de Compostela, 15782, Spain. + 00 34 881 815418 (CC); + 00 34 881 815420 (ML). Fax: + 34 881815403. E-mail: cristina.contreras@ 123456usc.es ; m.lopez@ 123456usc.es
                Article
                919727
                10.3109/07853890.2014.919727
                4438385
                24915455
                da7575d2-f3a6-488e-b6bc-8f3fae430def
                © 2015 The Author(s). Published by Taylor & Francis.

                This is an open access article distributed under the Supplemental Terms and Conditions for iOpenAccess articles published in Taylor & Francis journals , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                : 25 December 2013
                : 25 April 2014
                Page count
                Figures: 3, Tables: 0, References: 365, Pages: 19
                Categories
                Special Selection: Brown Fat

                Medicine
                ampk,β-adrenoreceptors,brown adipose tissue (bat),hypothalamus,obesity,orexins,sympathetic nervous system (sns),thermogenesis,thyroid hormone,uncoupling protein 1 (ucp1)

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