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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Blotting, Western
  • Body Weight / drug effects
  • Body Weight / genetics
  • Body Weight / physiology*
  • Cells, Cultured
  • Central Nervous System / cytology*
  • Central Nervous System / drug effects
  • Central Nervous System / enzymology*
  • Dependovirus / genetics
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Fatty Acids, Nonesterified / blood
  • Female
  • Fluorescent Antibody Technique
  • Glucosyltransferases / genetics
  • Glucosyltransferases / metabolism*
  • Homeostasis / drug effects
  • Homeostasis / genetics
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Immunoprecipitation
  • Leptin / blood
  • Male
  • Mice
  • Mice, Mutant Strains
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Motor Activity / physiology
  • Neurons / drug effects
  • Neurons / enzymology*

Substances

  • Fatty Acids, Nonesterified
  • Leptin
  • Glucosyltransferases
  • ceramide glucosyltransferase

Grant support

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.