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PLoS Biol. 2013;11(3):e1001506. doi: 10.1371/journal.pbio.1001506. Epub 2013 Mar 12.

Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

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  • 1Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. v.nordstroem@dkfz-heidelberg.de

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.

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PMID:
23554574
[PubMed - indexed for MEDLINE]
PMCID:
PMC3595213
Free PMC Article
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