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Kim, Jung Dae; Toda, Chitoku; D'Agostino, Giuseppe; Zeiss, Caroline J.; DiLeone, Ralph J.; Elsworth, John D.; Kibbey, Richard G.; Chan, Owen; Harvey, Brandon K.; Richie, Christopher T.; Savolainen, Mari; Myöhännen, Timo; Jeong, Jin Kwon; Diano, Sabrina

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

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  • Medientyp: E-Artikel
  • Titel: Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
  • Beteiligte: Kim, Jung Dae; Toda, Chitoku; D'Agostino, Giuseppe; Zeiss, Caroline J.; DiLeone, Ralph J.; Elsworth, John D.; Kibbey, Richard G.; Chan, Owen; Harvey, Brandon K.; Richie, Christopher T.; Savolainen, Mari; Myöhännen, Timo; Jeong, Jin Kwon; Diano, Sabrina
  • Erschienen: National Academy of Sciences, 2014
  • Erschienen in: Proceedings of the National Academy of Sciences of the United States of America
  • Sprache: Englisch
  • DOI: 10.1073/pnas.1406000111
  • ISSN: 0027-8424
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <p>Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prepgt/gt) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prepgt/gt and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prepgt/gt and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prepgt/gt mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus–PREP reversed the glucose-intolerant phenotype of the Prepgt/gt mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.</p>
  • Zugangsstatus: Freier Zugang