Enhanced Hypothalamic Glucose Sensing in Obesity: Alteration of Redox Signaling

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 10; pp. 2189 - 2197
• Main Authors: COLOMBANI, Anne-Laure, CARNEIRO, Lionel, PENICAUD, Luc, LELOUP, Corinne, BENANI, Alexandre, GALINIER, Anne, JAILLARD, Tristan, DUPARC, Thibaut, OFFER, Géraldine, LORSIGNOL, Anne, MAGNAN, Christophe, CASTEILLA, Louis
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2009
• Subjects: Aconitate Hydratase - metabolism; Action Potentials - drug effects; Animals; Biological and medical sciences; Blood glucose test; Brain - drug effects; Brain - physiology; Brain - physiopathology; Brain research; Cellular signal transduction; Complications and side effects; Diabetes. Impaired glucose tolerance; Diagnosis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Glucose - pharmacology; Health aspects; Homeostasis; Hypersensitivity - metabolism; Hypersensitivity - physiopathology; Hypothalamus - drug effects; Hypothalamus - physiology; Hypothalamus - physiopathology; Insulin resistance; Male; Medical sciences; Metabolic diseases; Metabolism; Metabolites; Mitochondria - drug effects; Mitochondria - physiology; Mitochondrial diseases; Obesity; Obesity - genetics; Obesity - physiopathology; Original; Oxidation-Reduction; Oxidative Phosphorylation - drug effects; Oxygen Consumption - drug effects; Physiological aspects; Physiology; Rats; Rats, Zucker; Research design; Signal Transduction; France; Endocrinopathy; Obesity; Signal transduction; Diabetes mellitus; Central nervous system; Nutrition disorder; Glucose; Hypothalamus; Nutritional status; Encephalon
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0110

Enhanced Hypothalamic Glucose Sensing in Obesity: Alteration of Redox Signaling Anne-Laure Colombani 1 , Lionel Carneiro 1 , Alexandre Benani 1 , Anne Galinier 1 , Tristan Jaillard 1 , Thibaut Duparc 1 , Géraldine Offer 1 , Anne Lorsignol 1 , Christophe Magnan 2 , Louis Casteilla 1 , Luc Pénicaud 1 and Corinne Leloup 1 1 Métabolisme, Plasticité et Mitochondrie, Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France; 2 Physiopathologie de la Nutrition, Unité Mixte de Recherche 7059, Centre National de la Recherche Scientifique, Université Denis Diderot, Paris, France. Corresponding author: Corinne Leloup, leloup{at}cict.fr . 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. RESEARCH DESIGN AND 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received January 25, 2009. Accepted June 22, 2009. © 2009 by the American Diabetes Association.