title: Astrocytes Regulate GLP-1 Receptor-Mediated Effects on Energy Balance.
abstract: Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control. This effect is mediated by GLP-1R, as the uptake of systemically administered fluorophore-tagged exendin-4 was blocked by central pretreatment with the competitive GLP-1R antagonist exendin-(9-39). Ex vivo analyses show prolonged exendin-4-induced activation (live cell calcium signaling) of NTS astrocytes and neurons; these effects are also attenuated by exendin-(9-39), indicating mediation by the GLP-1R. In vitro analyses show that the application of GLP-1R agonists increases cAMP levels in astrocytes. Immunohistochemical analyses reveal that endogenous GLP-1 axons form close synaptic apposition with NTS astrocytes. Finally, pharmacological inhibition of NTS astrocytes attenuates the anorectic and body weight-suppressive effects of intra-NTS GLP-1R activation. Collectively, data demonstrate a role for NTS astrocytic GLP-1R signaling in energy balance control.
  
  
  CONCLUSIONS
  Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are approved by the Food and Drug Administration for the treatment of obesity, but the cellular mechanisms underlying the anorectic effects of GLP-1 require further investigation. Astrocytes represent a major cellular population in the CNS that regulates neurotransmission, yet the role of astrocytes in mediating energy balance is largely unstudied. The current data provide novel evidence that astrocytes within the NTS are relevant for energy balance control by GLP-1 signaling. Here, we report that GLP-1R agonists activate and internalize within NTS astrocytes, while behavioral data suggest the pharmacological relevance of NTS astrocytic GLP-1R activation for food intake and body weight. These findings support a previously unknown role for CNS astrocytes in energy balance control by GLP-1 signaling.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Reiner
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Mietlicki-Baase
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McGrath
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Zimmer
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Bence
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Sousa
authors.affiliation: Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California 90089, and.
authors.forename: Vaibhav R
authors.initials: VR
authors.lastname: Konanur
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and.
authors.forename: Joanna
authors.identifier: http://orcid.org/0000-0001-8263-1890
authors.initials: J
authors.lastname: Krawczyk
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808.
authors.forename: David H
authors.initials: DH
authors.lastname: Burk
authors.affiliation: Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California 90089, and.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kanoski
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808.
authors.forename: Gerlinda E
authors.identifier: http://orcid.org/0000-0003-0405-2820
authors.initials: GE
authors.lastname: Hermann
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Rogers
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, and hayesmr@mail.med.upenn.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D001253:Astrocytes / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor
keywords: GLP-1; astrocyte; exendin-4; food intake; liraglutide; obesity