title: Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice.
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.
authors: Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism.
authors: Jung Dae
authors: JD
authors: Kim
authors: Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism.
authors: Chitoku
authors: C
authors: Toda
authors: Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism.
authors: Giuseppe
authors: G
authors: D'Agostino
authors: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors: Caroline J
authors: CJ
authors: Zeiss
authors: Psychiatry.
authors: Ralph J
authors: RJ
authors: DiLeone
authors: Psychiatry.
authors: John D
authors: JD
authors: Elsworth
authors: Internal Medicine,Cellular and Molecular Physiology.
authors: Richard G
authors: RG
authors: Kibbey
authors: Internal Medicine.
authors: Owen
authors: O
authors: Chan
authors: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; and.
authors: Brandon K
authors: BK
authors: Harvey
authors: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; and.
authors: Christopher T
authors: CT
authors: Richie
authors: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; andFaculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland.
authors: Mari
authors: M
authors: Savolainen
authors: Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland.
authors: Timo
authors: T
authors: Myöhänen
authors: Departments of Obstetrics, Gynecology, and Reproductive Sciences,Program in Integrative Cell Signaling and Neurobiology of Metabolism.
authors: Jin Kwon
authors: JK
authors: Jeong
authors: 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.
authors: Sabrina
authors: S
authors: Diano
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005934:Glucagon / Q000378:metabolism*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000201:enzymology / Q000209:etiology; D007031:Hypothalamus / Q000201:enzymology* / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics; D010179:Pancreas / Q000378:metabolism; D010766:Phosphorylation; D000085822:Prolyl Oligopeptidases; D011972:Receptor, Insulin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007211:Indoles; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C118986:S 17092-1; D015842:Serine Proteinase Inhibitors; D053778:Thiazolidines; D000071256:Uncoupling Protein 1; D005934:Glucagon; D011972:Receptor, Insulin; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases
keywords: central glucose sensing; peripheral hormonal regulation; sympathetic nervous system