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      5-HT 2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis

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          Summary

          Drugs activating 5-hydroxytryptamine 2C receptors (5-HT 2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT 2CR deficiency ( 2C null) and mice with 5-HT 2CRs re-expression only in pro-opiomelanocortin (POMC) neurons ( 2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT 2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT 2CR-melanocortin circuitry in the long-term regulation of energy balance.

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          Anatomy and regulation of the central melanocortin system.

          Roger Cone (2005)
          The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
          Article 0 comments Cited 315 times – based on 0 reviews     Review now
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            The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C.

            Shivendra Kishore, Stefan Stamm (2006)
            The Prader-Willi syndrome is a congenital disease that is caused by the loss of paternal gene expression from a maternally imprinted region on chromosome 15. This region contains a small nucleolar RNA (snoRNA), HBII-52, that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor 5-HT(2C)R. We found that HBII-52 regulates alternative splicing of 5-HT(2C)R by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different 5-HT(2C)R messenger RNA (mRNA) isoforms than healthy individuals. Our results show that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.
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              Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.

              L. Tecott, L. Sun, S. F. AKANA … (1995)
              Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.
              Article 0 comments Cited 182 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neuron
                Title: Neuron
                Publisher: Cell Press
                ISSN (Print): 0896-6273
                ISSN (Electronic): 1097-4199
                Publication date PMC-release: 26 November 2008
                Publication date (Print): 26 November 2008
                Volume: 60
                Issue: 4-2
                Pages: 582-589
                Affiliations
                [1 ]Division of Hypothalamic Research, Departments of Internal Medicine, Pharmacology, and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
                [2 ]Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
                [3 ]Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
                Author notes
                [∗ ]Corresponding author joel.elmquist@ 123456utsouthwestern.edu
                [4]

                These authors contributed equally to this work

                Article
                Publisher ID: NEURON3522
                DOI: 10.1016/j.neuron.2008.09.033
                PMC ID: 2631191
                PubMed ID: 19038216
                SO-VID: a65eeffa-aff0-42c2-9698-1bb4b22fede0
                Copyright © © 2008 ELL & Excerpta Medica.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date accepted : 9 September 2008
                Categories
                Subject: Report

                ScienceOpen disciplines: Neurosciences
                Keywords: humdisease,signaling,molneuro
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: humdisease, signaling, molneuro

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