title: Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.
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.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. v.nordstroem@dkfz-heidelberg.de
authors.forename: Viola
authors.initials: V
authors.lastname: Nordström
authors.forename: Monja
authors.initials: M
authors.lastname: Willershäuser
authors.forename: Silke
authors.initials: S
authors.lastname: Herzer
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.forename: Sascha
authors.initials: S
authors.lastname: Meldner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Rothermel
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kaden
authors.forename: Fabian C
authors.initials: FC
authors.lastname: Roth
authors.forename: Clemens
authors.initials: C
authors.lastname: Waldeck
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Richard
authors.initials: R
authors.lastname: Jennemann
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D000229:Dependovirus / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005455:Fluorescent Antibody Technique; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects; D047468:Immunoprecipitation; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*
chemical_list: D005230:Fatty Acids, Nonesterified; D020738:Leptin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
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