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      Neuronal Expression of Glucosylceramide Synthase in Central Nervous System Regulates Body Weight and Energy Homeostasis

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          Abstract

          Body weight and energy homeostasis are regulated by leptin receptor interactions with gangliosides, a class of plasma membrane lipids, in forebrain neurons of mice.

          Abstract

          Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene ( Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

          Author Summary

          Obesity is a growing health threat that affects nearly half a billion people worldwide, and its incidence rates in lower income countries are rising dramatically. As obesity is a major risk factor for type II diabetes and cardiovascular disease, significant effort has been put into the exploration of causes, prevention, and potential treatment. Recent research has demonstrated that a region of the brain called the hypothalamus is a major integrator of metabolic and nutrient signals, adapting food intake and energy expenditure to current metabolic needs. Leptin or insulin receptors located in the plasma cell membrane of neurons sense energy signals from the body. They transmit this information inside the cell, which then regulates neuronal function. In this study, we show that leptin receptors interact with gangliosides, a class of plasma membrane lipids. This interaction is a prerequisite for proper receptor activation. Consequently, ganglioside loss in hypothalamic neurons inhibits leptin receptor signal transduction in response to energy metabolites. Furthermore, mice lacking gangliosides in distinct forebrain areas, amongst them the hypothalamus, develop progressive obesity and hypothermia. Our results suggest a previously unknown regulatory mechanism of plasma membrane lipids for hypothalamic control of body weight.

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Revitalizing membrane rafts: new tools and insights.

            Ten years ago, we wrote a Review on lipid rafts and signalling in the launch issue of Nature Reviews Molecular Cell Biology. At the time, this field was suffering from ambiguous methodology and imprecise nomenclature. Now, new techniques are deepening our insight into the dynamics of membrane organization. Here, we discuss how the field has matured and present an evolving model in which membranes are occupied by fluctuating nanoscale assemblies of sphingolipids, cholesterol and proteins that can be stabilized into platforms that are important in signalling, viral infection and membrane trafficking.
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              Abnormal splicing of the leptin receptor in diabetic mice.

              Mutations in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity. Previous data suggest that the db gene encodes the receptor for the obese (ob) gene product, leptin. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db. This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                March 2013
                March 2013
                12 March 2013
                : 11
                : 3
                : e1001506
                Affiliations
                [1 ]Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
                [2 ]German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
                [3 ]Molecular Nutritional Medicine, Else-Kröner Fresenius Center, Technische Universität München, Freising-Weihenstephan, Germany
                [4 ]Institute for Anatomy and Cell Biology, University of Greifswald, Greifswald, Germany
                [5 ]Institute for Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
                [6 ]Medical Research Center, Heidelberg University, Heidelberg, Germany
                University of Cambridge, United Kingdom
                Author notes

                The authors have declared that no competing interests exist.

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: VN HJG RJ MK JR AD MHA. Performed the experiments: VN MW SH SM UR SK FCR CW. Analyzed the data: VN MW JR FCR CW AD MK. Contributed reagents/materials/analysis tools: OBH NG. Wrote the paper: VN MW HJG JR MK.

                ¶ Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.

                Article
                PBIOLOGY-D-12-04780
                10.1371/journal.pbio.1001506
                3595213
                23554574
                c2b25297-f606-4307-b5e5-a9501dca8d83
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 November 2012
                : 31 January 2013
                Page count
                Pages: 19
                Funding
                This work was supported by the European Foundation for the Study of Diabetes (EFSD/Amylin grant to V.N.; http://www.europeandiabetesfoundation.org) and grants from the Deutsche Forschungsgemeinschaft (DFG; http://www.dfg.de) SFB 938, and GK 888 to H-J.G. Work at the German Mouse Clinic was supported by grants from the European Community (EUMODIC LSHG-2006-037188, Infrafrontier contract No. 211404 to the GMC; http://www.eumodic.org) to the GMC and from the Bundesministerium für Bildung und Forschung (NGFN-Plus: to M.K. [01GS0822, 01GS0869] and to M.H.A. [01GS0850]; http://www.ngfn.de), Infrafrontier (01KX1012 to the GMC and to the German Center for Diabetes Research [DZD e.V.]; http://www.infrafrontier.eu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Gene Function
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Signal Transduction
                Membrane Receptor Signaling
                Signaling Cascades
                Membranes and Sorting
                Neuroscience
                Neurochemistry
                Neuroendocrinology
                Cellular Neuroscience
                Proteomics
                Protein Interactions

                Life sciences
                Life sciences

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