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

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

Research output: Contribution to journalArticlepeer-review


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 (Prep(gt/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 Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/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 Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.
Original languageEnglish
Pages (from-to)11876-11881
Number of pages6
JournalProceedings of the National Academy of Sciences
Issue number32
Publication statusPublished - 12 Aug 2014


  • Animals
  • Blood Glucose
  • Gene Expression
  • Gene Knockdown Techniques
  • Glucagon
  • Glucose Clamp Technique
  • Glucose Intolerance
  • Hypothalamus
  • Indoles
  • Insulin
  • Ion Channels
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins
  • Pancreas
  • Phosphorylation
  • Receptor, Insulin
  • Recombinant Proteins
  • Serine Endopeptidases
  • Serine Proteinase Inhibitors
  • Thiazolidines
  • Ventromedial Hypothalamic Nucleus


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