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Orexin-A Inhibits Glucagon Secretion and Gene Expression through a Foxo1-Dependent Pathway

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie and Interdisziplinäres Stoffwechsel-Centrum (E.G., M.Z.S., C.G., S.M., B.W., U.P.), Endokrinologie, Diabetes, und Stoffwechsel, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany; Department of Animal Physiology and Biochemistry (K.W.N., P.K., M.S.), August Cieszkowski University of Agriculture, 60–637 Poznan, Poland; Klinik für Unfall-, Wiederherstellungs-, und Handchirurgie (B.F.E.-Z.), Philipps-Universität Marburg, D-35032 Marburg, Germany; and Department of Endocrinology (M.T., G.K.S.), Max-Planck-Institut für Psychiatrie, 80804 München, Germany

Address all correspondence and requests for reprints to: Ursula Plöckinger, M.D., Interdisziplinäres Stoffwechsel-Centrum: Endokrinologie, Diabetes, und Stoffwechsel Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: ursula.ploeckinger{at}charite.de.

Orexin-A (OXA) regulates food intake and energy homeostasis. It increases insulin secretion in vivo and in vitro, although controversial effects of OXA on plasma glucagon are reported. We characterized the effects of OXA on glucagon secretion and identify intracellular target molecules in glucagon-producing cells. Glucagon secretion from in situ perfused rat pancreas, isolated rat pancreatic islets, and clonal pancreatic A-cells (InR1-G9) were measured by RIA. The expression of orexin receptor 1 (OXR1) was detected by Western blot and immunofluorescence. The effects of OXA on cAMP, adenylate-cyclase-kinase (AKT), phosphoinositide-dependent kinase (PDK)-1, forkhead box O-1 (Foxo1), and cAMP response element-binding protein were measured by ELISA and Western blot. Intracellular calcium (Ca²⁺_i) concentration was detected by fura-2and glucagon expression by real-time PCR. Foxo1 was silenced in InR1-G9 cells by transfecting cells with short interfering RNA. OXR1 was expressed on pancreatic A and InR1-G9 cells. OXA reduced glucagon secretion from perfused rat pancreas, isolated rat pancreatic islets, and InR1-G9 cells. OXA inhibited proglucagon gene expression via the phosphatidylinositol 3-kinase-dependent pathway. OXA decreased cAMP and Ca²⁺_i concentration and increased AKT, PDK-1, and Foxo1 phosphorylation. Silencing of Foxo1 caused a reversal of the inhibitory effect of OXA on proglucagon gene expression. Our study provides the first in vitro evidence for the interaction of OXA with pancreatic A cells. OXA inhibits glucagon secretion and reduces intracellular cAMP and Ca²⁺_i concentration. OXA increases AKT/PDK-1 phosphorylation and inhibits proglucagon expression via phosphatidylinositol 3-kinase- and Foxo-1-dependent pathways. As a physiological inhibitor of glucagon secretion, OXA may have a therapeutic potential to reduce hyperglucagonemia in type 2 diabetes.

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