1. Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
- Author
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Jin Kwon Jeong, Jung Dae Kim, Mari Savolainen, Ralph J. DiLeone, Giuseppe D'Agostino, John D. Elsworth, Caroline J. Zeiss, Sabrina Diano, Timo T. Myöhänen, Owen Chan, Richard G. Kibbey, Chitoku Toda, Brandon K. Harvey, Christopher T. Richie, 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, Myöhänen, Timo, Jeong, Jin Kwon, and Diano, Sabrina
- Subjects
Blood Glucose ,Male ,Indoles ,medicine.medical_treatment ,Gene Expression ,Ion Channels ,Impaired glucose tolerance ,Mice ,0302 clinical medicine ,Ion Channel ,Insulin Secretion ,Hypothalamu ,Pancrea ,Insulin ,Thiazolidine ,Phosphorylation ,Uncoupling Protein 1 ,0303 health sciences ,Multidisciplinary ,Serine Endopeptidases ,Glucagon secretion ,Glucose clamp technique ,Recombinant Protein ,Biological Sciences ,Recombinant Proteins ,3. Good health ,Serine Endopeptidase ,peripheral hormonal regulation ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Thiazolidines ,Serine Proteinase Inhibitor ,Prolyl Oligopeptidases ,medicine.drug ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Hypothalamus ,Mice, Transgenic ,Carbohydrate metabolism ,Biology ,Glucagon ,Mitochondrial Proteins ,03 medical and health sciences ,central glucose sensing ,Prolyl endopeptidase ,Internal medicine ,Glucose Intolerance ,medicine ,Mitochondrial Protein ,Animals ,Pancreas ,030304 developmental biology ,sympathetic nervous system ,Animal ,Pancreatic islets ,medicine.disease ,Receptor, Insulin ,Endocrinology ,Indole ,Ventromedial Hypothalamic Nucleus ,Gene Knockdown Technique ,Glucose Clamp Technique ,030217 neurology & neurosurgery - 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.
- Published
- 2014