title: Hypothalamic apelin/reactive oxygen species signaling controls hepatic glucose metabolism in the onset of diabetes.
abstract: OBJECTIVE
  We have previously demonstrated that central apelin is implicated in the control of peripheral glycemia, and its action depends on nutritional (fast versus fed) and physiological (normal versus diabetic) states. An intracerebroventricular (icv) injection of a high dose of apelin, similar to that observed in obese/diabetic mice, increase fasted glycemia, suggesting (i) that apelin contributes to the establishment of a diabetic state, and (ii) the existence of a hypothalamic to liver axis. Using pharmacological, genetic, and nutritional approaches, we aim at unraveling this system of regulation by identifying the hypothalamic molecular actors that trigger the apelin effect on liver glucose metabolism and glycemia.
  
  
  RESULTS
  We show that icv apelin injection stimulates liver glycogenolysis and gluconeogenesis via an over-activation of the sympathetic nervous system (SNS), leading to fasted hyperglycemia. The effect of central apelin on liver function is dependent of an increased production of hypothalamic reactive oxygen species (ROS). These data are strengthened by experiments using lentiviral vector-mediated over-expression of apelin in hypothalamus of mice that present over-activation of SNS associated to an increase in hepatic glucose production. Finally, we report that mice fed a high-fat diet present major alterations of hypothalamic apelin/ROS signaling, leading to activation of glycogenolysis. INNOVATION/CONCLUSION: These data bring compelling evidence that hypothalamic apelin is one master switch that participates in the onset of diabetes by directly acting on liver function. Our data support the idea that hypothalamic apelin is a new potential therapeutic target to treat diabetes.
authors.affiliation: 1 Institut National de la Santé et de la Recherche Médicale (INSERM) , Toulouse, France .
authors.forename: Anne
authors.initials: A
authors.lastname: Drougard
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.forename: Xavier
authors.initials: X
authors.lastname: Brenachot
authors.forename: Lionel
authors.initials: L
authors.lastname: Carneiro
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gouazé
authors.forename: Audren
authors.initials: A
authors.lastname: Fournel
authors.forename: Lucie
authors.initials: L
authors.lastname: Geurts
authors.forename: Thomas
authors.initials: T
authors.lastname: Cadoudal
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Prats
authors.forename: Luc
authors.initials: L
authors.lastname: Pénicaud
authors.forename: Didier
authors.initials: D
authors.lastname: Vieau
authors.forename: Jean
authors.initials: J
authors.lastname: Lesage
authors.forename: Corinne
authors.initials: C
authors.lastname: Leloup
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benani
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D001341:Autonomic Nervous System; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis; D007031:Hypothalamus / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D001786:Blood Glucose; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D005947:Glucose