title: Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling.
abstract: OBJECTIVE
  Recent data demonstrated that glucose sensing in different tissues is initiated by an intracellular redox signaling pathway in physiological conditions. However, the relevance of such a mechanism in metabolic disease is not known. The aim of the present study was to determine whether brain glucose hypersensitivity present in obese Zücker rats is related to an alteration in redox signaling.
  
  
  METHODS
  Brain glucose sensing alteration was investigated in vivo through the evaluation of electrical activity in arcuate nucleus, changes in reactive oxygen species levels, and hypothalamic glucose-induced insulin secretion. In basal conditions, modifications of redox state and mitochondrial functions were assessed through oxidized glutathione, glutathione peroxidase, manganese superoxide dismutase, aconitase activities, and mitochondrial respiration.
  
  
  RESULTS
  Hypothalamic hypersensitivity to glucose was characterized by enhanced electrical activity of the arcuate nucleus and increased insulin secretion at a low glucose concentration, which does not produce such an effect in normal rats. It was associated with 1) increased reactive oxygen species levels in response to this low glucose load, 2) constitutive oxidized environment coupled with lower antioxidant enzyme activity at both the cellular and mitochondrial level, and 3) overexpression of several mitochondrial subunits of the respiratory chain coupled with a global dysfunction in mitochondrial activity. Moreover, pharmacological restoration of the glutathione hypothalamic redox state by reduced glutathione infusion in the third ventricle fully reversed the cerebral hypersensitivity to glucose.
  
  
  CONCLUSIONS
  The data demonstrated that obese Zücker rats' impaired hypothalamic regulation in terms of glucose sensing is linked to an abnormal redox signaling, which originates from mitochondria dysfunction.
authors: Métabolisme, Plasticité et Mitochondrie, Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France.
authors: Anne-Laure
authors: AL
authors: Colombani
authors: Lionel
authors: L
authors: Carneiro
authors: Alexandre
authors: A
authors: Benani
authors: Anne
authors: A
authors: Galinier
authors: Tristan
authors: T
authors: Jaillard
authors: Thibaut
authors: T
authors: Duparc
authors: Géraldine
authors: G
authors: Offer
authors: Anne
authors: A
authors: Lorsignol
authors: Christophe
authors: C
authors: Magnan
authors: Louis
authors: L
authors: Casteilla
authors: Luc
authors: L
authors: Pénicaud
authors: Corinne
authors: C
authors: Leloup
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis; D006967:Hypersensitivity / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction
chemical_list: D000154:Aconitate Hydratase; D005947:Glucose