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

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

Author information

1
Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism.
2
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520;
3
Psychiatry.
4
Internal Medicine,Cellular and Molecular Physiology.
5
Internal Medicine.
6
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; and.
7
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; andFaculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland.
8
Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland.
9
Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism,Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520;Neurobiology, sabrina.diano@yale.edu.

Erratum in

  • Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):14003.

Abstract

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

PMID:
25071172
PMCID:
PMC4136568
DOI:
10.1073/pnas.1406000111
[Indexed for MEDLINE]
Free PMC Article

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