Hypothalamic apelin/reactive oxygen species signaling controls hepatic glucose metabolism in the onset of diabetes
2014
Drougard, Anne | Duparc, Thibaut | Brenachot, Xavier | Carneiro, Lionel | Gouazé, Alexandra | Fournel, Audren | Geurts, Lucie | Cadoudal, Thomas | Prats, Anne-Catherine | Penicaud, Luc | Vieau, Didier | Lesage, Jean | Amiot Leloup, Corinne | Benani, Alexandre | Cani, Patrice D. | Valet, Philippe | Knauf, Claude | Faculté de Médecine [Rangueil] ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) | Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA) ; Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS) | Université de Bourgogne (UB) | Catholic Univ Louvain, LDRI, Metab & Nutr Res Grp, B-1200 Brussels, Belgium ; Université Catholique de Louvain = Catholic University of Louvain (UCL) | Contrôle de la Traduction et Thérapie Génique des Pathologies Vasculaires (TRADGENE) ; Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT) | Environnement périnatal et croissance - EA 4489 (EPS) ; Université de Lille-Centre Hospitalier Régional Universitaire [CHU Lille] (CHRU Lille)
Aims: 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.
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