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

Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11876-81. doi: 10.1073/pnas.1406000111. Epub 2014 Jul 28.


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.

Keywords: central glucose sensing; peripheral hormonal regulation; sympathetic nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Gene Expression
  • Gene Knockdown Techniques
  • Glucagon / metabolism*
  • Glucose Clamp Technique
  • Glucose Intolerance / enzymology
  • Glucose Intolerance / etiology
  • Hypothalamus / enzymology*
  • Hypothalamus / physiology
  • Indoles / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Ion Channels / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics
  • Pancreas / metabolism
  • Phosphorylation
  • Prolyl Oligopeptidases
  • Receptor, Insulin / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / pharmacology
  • Thiazolidines / pharmacology
  • Uncoupling Protein 1
  • Ventromedial Hypothalamic Nucleus / enzymology
  • Ventromedial Hypothalamic Nucleus / physiology


  • Blood Glucose
  • Indoles
  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • Recombinant Proteins
  • S 17092-1
  • Serine Proteinase Inhibitors
  • Thiazolidines
  • Uncoupling Protein 1
  • Glucagon
  • Receptor, Insulin
  • Serine Endopeptidases
  • Prolyl Oligopeptidases