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

Viola Nordström, Monja Willershäuser, Silke Herzer, Jan Rozman, Oliver von Bohlen und Halbach, Sascha Meldner, Ulrike Rothermel, Sylvia Kaden, Fabian C. Roth, Clemens Waldeck, Norbert Gretz, Martin Hrabě de Angelis, Andreas Draguhn, Martin Klingenspor, Hermann Josef Gröne, Richard Jennemann

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54 Scopus citations

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.

Original languageEnglish
Article numbere1001506
JournalPLoS Biology
Volume11
Issue number3
DOIs
StatePublished - Mar 2013

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