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Orexin-A inhibits glucagon secretion and gene expression through a Foxo1-dependent pathway

Eva Göncz1, Mathias Z Strowski, Carsten Grötzinger

  • 1Endokrinologie, Diabetes, und Stoffwechsel Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.

Endocrinology
|December 29, 2007
PubMed

Insights

Orexin-A (OXA) inhibits glucagon secretion from pancreatic A-cells by reducing cAMP and calcium levels. This pathway involves AKT/PDK-1 phosphorylation and Foxo1, suggesting OXA

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Orexin-A (OXA) is known to regulate food intake and energy homeostasis.
  • Its effects on insulin secretion are established, but its role in regulating glucagon secretion remains controversial.
  • Understanding OXA's impact on pancreatic A-cells is crucial for metabolic research.

Purpose of the Study:

  • To investigate the effects of Orexin-A (OXA) on glucagon secretion from pancreatic A-cells.
  • To identify the intracellular molecular targets and signaling pathways involved in OXA's action on these cells.
  • To explore the potential therapeutic role of OXA in conditions like type 2 diabetes.

Main Methods:

  • Measurements of glucagon secretion using RIA in perfused rat pancreas, isolated islets, and clonal pancreatic A-cells (InR1-G9).
  • Detection of orexin receptor 1 (OXR1) expression via Western blot and immunofluorescence.
  • Assays for intracellular signaling molecules (cAMP, AKT, PDK-1, Foxo1) and calcium concentration (Ca(2+)(i)).
  • Gene expression analysis of proglucagon and functional studies involving Foxo1 silencing using short interfering RNA.

Main Results:

  • Orexin receptor 1 (OXR1) was confirmed to be expressed on pancreatic A-cells.
  • OXA significantly reduced glucagon secretion across all tested models (perfused pancreas, isolated islets, clonal A-cells).
  • OXA inhibited proglucagon gene expression, decreased intracellular cAMP and Ca(2+)(i) levels, and increased AKT, PDK-1, and Foxo1 phosphorylation.
  • Silencing Foxo1 reversed the inhibitory effect of OXA on proglucagon gene expression, highlighting its critical role.

Conclusions:

  • This study provides the first in vitro evidence of Orexin-A (OXA) interacting with pancreatic A-cells.
  • OXA acts as a physiological inhibitor of glucagon secretion by modulating intracellular cAMP and calcium levels.
  • The mechanism involves the phosphatidylinositol 3-kinase (PI3K)/AKT/PDK-1 pathway, leading to Foxo1 phosphorylation and subsequent inhibition of proglucagon expression.
  • OXA demonstrates therapeutic potential for reducing hyperglucagonemia in type 2 diabetes.

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