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Glucagon regulates its own synthesis by autocrine signaling.

ABSTRACT: Peptide hormones are powerful regulators of various biological processes. To guarantee continuous availability and function, peptide hormone secretion must be tightly coupled to its biosynthesis. A simple but efficient way to provide such regulation is through an autocrine feedback mechanism in which the secreted hormone is "sensed" by its respective receptor and initiates synthesis at the level of transcription and/or translation. Such a secretion-biosynthesis coupling has been demonstrated for insulin; however, because of insulin's unique role as the sole blood glucose-decreasing peptide hormone, this coupling is considered an exception rather than a more generally used mechanism. Here we provide evidence of a secretion-biosynthesis coupling for glucagon, one of several peptide hormones that increase blood glucose levels. We show that glucagon, secreted by the pancreatic ? cell, up-regulates the expression of its own gene by signaling through the glucagon receptor, PKC, and PKA, supporting the more general applicability of an autocrine feedback mechanism in regulation of peptide hormone synthesis.

SUBMITTER: Leibiger B

PROVIDER: S-EPMC3529083 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Glucagon regulates its own synthesis by autocrine signaling.

Leibiger Barbara B Moede Tilo T Muhandiramlage Thusitha P TP Kaiser Daniel D Vaca Sanchez Pilar P Leibiger Ingo B IB Berggren Per-Olof PO

Proceedings of the National Academy of Sciences of the United States of America 20121203 51

Peptide hormones are powerful regulators of various biological processes. To guarantee continuous availability and function, peptide hormone secretion must be tightly coupled to its biosynthesis. A simple but efficient way to provide such regulation is through an autocrine feedback mechanism in which the secreted hormone is "sensed" by its respective receptor and initiates synthesis at the level of transcription and/or translation. Such a secretion-biosynthesis coupling has been demonstrated for ...[more]

PMID: 23213228

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Project description:The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial ?-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced ?-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-?, IL-1?, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-?, IL-1?, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and ?-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated ?-endorphin expression in cultured primary microglia, whereas treatment with ?-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of ?-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38?, but not siRNA/p38?, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-? mRNA using siRNA fully inhibited exenatide-induced spinal microglial ?-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and ?-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated ?-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38?/CREB and subsequent IL-10 receptor/STAT3 signal pathways.SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor ?-endorphin from microglia. GLP-1 receptor agonism induces ?-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and ?-endorphin expression subsequently through the Gs-cAMP/PKA/p38?/CREB and IL-10/IL-10 receptor-?/STAT3 signal transduction pathways.

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Glucagon regulates its own synthesis by autocrine signaling.

Publications

Glucagon regulates its own synthesis by autocrine signaling.

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