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

doi:10.1073/pnas.1406000111

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

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22 Citations (Scopus)

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.

Original language	English
Pages (from-to)	11876-11881
Number of pages	6
Journal	PNAS
Volume	111
Issue number	32
Early online date	28 Jul 2014
DOIs	https://doi.org/10.1073/pnas.1406000111
Publication status	Published - 12 Aug 2014

Keywords

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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10.1073/pnas.1406000111

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Kim, J. D., Toda, C., D'Agostino, G., Zeiss, C. J., DiLeone, R. J., Elsworth, J. D., Kibbey, R. G., Chan, O., Harvey, B. K., Richie, C. T., Savolainen, M., Myöhänen, T., Jeong, J. K., & Diano, S. (2014). Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice. PNAS, 111(32), 11876-11881. https://doi.org/10.1073/pnas.1406000111

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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.",

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author = "Kim, {Jung Dae} and Chitoku Toda and Giuseppe D'Agostino and Zeiss, {Caroline J} and DiLeone, {Ralph J} and Elsworth, {John D} and Kibbey, {Richard G} and Owen Chan and Harvey, {Brandon K} and Richie, {Christopher T} and Mari Savolainen and Timo My{\"o}h{\"a}nen and Jeong, {Jin Kwon} and Sabrina Diano",

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TY - JOUR

T1 - Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

AU - Kim, Jung Dae

AU - Toda, Chitoku

AU - D'Agostino, Giuseppe

AU - Zeiss, Caroline J

AU - DiLeone, Ralph J

AU - Elsworth, John D

AU - Kibbey, Richard G

AU - Chan, Owen

AU - Harvey, Brandon K

AU - Richie, Christopher T

AU - Savolainen, Mari

AU - Myöhänen, Timo

AU - Jeong, Jin Kwon

AU - Diano, Sabrina

PY - 2014/8/12

Y1 - 2014/8/12

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Glucose

KW - Gene Expression

KW - Gene Knockdown Techniques

KW - Glucagon

KW - Glucose Clamp Technique

KW - Glucose Intolerance

KW - Hypothalamus

KW - Indoles

KW - Insulin

KW - Ion Channels

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Mitochondrial Proteins

KW - Pancreas

KW - Phosphorylation

KW - Receptor, Insulin

KW - Recombinant Proteins

KW - Serine Endopeptidases

KW - Serine Proteinase Inhibitors

KW - Thiazolidines

KW - Ventromedial Hypothalamic Nucleus

U2 - 10.1073/pnas.1406000111

DO - 10.1073/pnas.1406000111

M3 - Article

C2 - 25071172

VL - 111

SP - 11876

EP - 11881

JO - PNAS

JF - PNAS

SN - 0027-8424

IS - 32

ER -

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

Abstract

Keywords

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