title: Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling.
abstract: The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity.
  
  
  
  Herein we investigated whether decreased Endo1 expression in the hypothalamic ARC, associated with reduced obesity, could also ameliorate glucose homeostasis accordingly.
  
  
  
  We studied glucose homeostasis in lean or obese mice silenced for Endo1 in the ARC via stereotactic injection of shRNA-expressing lentiviral vectors.
  
  
  
  We observed that despite being leaner, Endo1-silenced mice showed impaired glucose homeostasis on HFD. Mechanistically, we show that Endo1 interacts with p85, the regulatory subunit of PI3K, and mediates leptin-induced PI3K activation.
  
  
  
  Our results thus define Endo1 as an important hypothalamic integrator of leptin signaling, and its silencing differentially regulates the OBR-dependent functions.
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Vauthier
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Roujeau
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: Patty
authors.initials: P
authors.lastname: Chen
authors.affiliation: University Paris Pierre et Marie Curie (UPMC), CNRS UMR 7091, NewVectys, Paris, France.
authors.forename: Chamsy
authors.initials: C
authors.lastname: Sarkis
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, CNRS UMR8251, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Migrenne
authors.affiliation: Hiroshima University, Hiroshima, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoi
authors.affiliation: Hiroshima University, Hiroshima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ozawa
authors.affiliation: University of Lille, CNRS UMR 8204, Inserm U1019, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Rouillé
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: University Paris Pierre et Marie Curie (UPMC), CNRS UMR 7091, NewVectys, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Université Paris Descartes, Inserm U942, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, CNRS UMR8251, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.affiliation: Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France. Electronic address: julie.dam@inserm.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Dam
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; C484581:Obrgrp protein, mouse; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D005947:Glucose
keywords: ARC, arcuate nucleus; BW, body weight; CD, chow diet; DIO, diet-induced obesity; Diabetes; Endo1, Endospanin1; GTT, glucose tolerance test; HFD, high fat diet; Insulin; LIF, leukemia inhibitory factor; Leptin receptor; OB-RGRP/Endospanin1; OBR, leptin receptor; Obesity; PLA, proximity ligation assay; T2D, type 2 diabetes; ip, intraperitoneal