Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
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...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (32), p.11876-11881 |
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| creator | 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 Myöhännen, Timo Jeong, Jin Kwon Diano, Sabrina |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1406000111 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1406000111</identifier><identifier>PMID: 25071172</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; autonomic nervous system ; Biological Sciences ; Blood Glucose - metabolism ; Brain ; Fasting ; Gene Expression ; Gene expression regulation ; Gene Knockdown Techniques ; Genotype & phenotype ; glucagon ; Glucagon - metabolism ; Glucose ; Glucose Clamp Technique ; Glucose Intolerance - enzymology ; Glucose Intolerance - etiology ; glucose tolerance ; Glucose tolerance test ; Hypothalamic regulation ; Hypothalamus ; Hypothalamus - enzymology ; Hypothalamus - physiology ; Indoles - pharmacology ; Insulin ; Insulin - metabolism ; Insulin Secretion ; Ion Channels - genetics ; islets of Langerhans ; Male ; mechanism of action ; Messenger RNA ; Mice ; Mice, Transgenic ; Mitochondrial Proteins - genetics ; Mode of action ; Nervous system ; norepinephrine ; Pancreas ; Pancreas - metabolism ; phenotype ; Phosphorylation ; propranolol ; Receptor, Insulin - metabolism ; Receptors ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Rodents ; 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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-08, Vol.111 (32), p.11876-11881</ispartof><rights>copyright © 1993—2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 12, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-25c5a2b6e96eed48064cecca3805bdc7dcad0c1c2c22df2ca244c7acdb6e4c963</citedby><cites>FETCH-LOGICAL-c624t-25c5a2b6e96eed48064cecca3805bdc7dcad0c1c2c22df2ca244c7acdb6e4c963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/32.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42919115$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42919115$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25071172$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Jung Dae</creatorcontrib><creatorcontrib>Toda, Chitoku</creatorcontrib><creatorcontrib>D'Agostino, Giuseppe</creatorcontrib><creatorcontrib>Zeiss, Caroline J.</creatorcontrib><creatorcontrib>DiLeone, Ralph J.</creatorcontrib><creatorcontrib>Elsworth, John D.</creatorcontrib><creatorcontrib>Kibbey, Richard G.</creatorcontrib><creatorcontrib>Chan, Owen</creatorcontrib><creatorcontrib>Harvey, Brandon K.</creatorcontrib><creatorcontrib>Richie, Christopher T.</creatorcontrib><creatorcontrib>Savolainen, Mari</creatorcontrib><creatorcontrib>Myöhännen, Timo</creatorcontrib><creatorcontrib>Jeong, Jin Kwon</creatorcontrib><creatorcontrib>Diano, Sabrina</creatorcontrib><title>Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Animals</subject><subject>autonomic nervous system</subject><subject>Biological Sciences</subject><subject>Blood Glucose - metabolism</subject><subject>Brain</subject><subject>Fasting</subject><subject>Gene Expression</subject><subject>Gene expression regulation</subject><subject>Gene Knockdown Techniques</subject><subject>Genotype & phenotype</subject><subject>glucagon</subject><subject>Glucagon - metabolism</subject><subject>Glucose</subject><subject>Glucose Clamp Technique</subject><subject>Glucose Intolerance - enzymology</subject><subject>Glucose Intolerance - etiology</subject><subject>glucose tolerance</subject><subject>Glucose tolerance test</subject><subject>Hypothalamic regulation</subject><subject>Hypothalamus</subject><subject>Hypothalamus - enzymology</subject><subject>Hypothalamus - physiology</subject><subject>Indoles - pharmacology</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Ion Channels - genetics</subject><subject>islets of Langerhans</subject><subject>Male</subject><subject>mechanism of action</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mode of action</subject><subject>Nervous system</subject><subject>norepinephrine</subject><subject>Pancreas</subject><subject>Pancreas - metabolism</subject><subject>phenotype</subject><subject>Phosphorylation</subject><subject>propranolol</subject><subject>Receptor, Insulin - metabolism</subject><subject>Receptors</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Rodents</subject><subject>Serine Endopeptidases - deficiency</subject><subject>Serine Endopeptidases - genetics</subject><subject>Serine Endopeptidases - metabolism</subject><subject>Serine Proteinase Inhibitors - pharmacology</subject><subject>Thiazolidines - pharmacology</subject><subject>Uncoupling Protein 1</subject><subject>Ventromedial Hypothalamic Nucleus - enzymology</subject><subject>Ventromedial Hypothalamic Nucleus - physiology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1v1DAQxSMEokvhzAmIxKUctp2xHSe-IKGqUKRKVEDP1qztTbPK2sFOkPa_x9Euy8elp7H0fu9pZjxF8RLhHKHmF4OndI4CJAAg4qNigaBwKYWCx8UCgNXLRjBxUjxLaZMZVTXwtDhhFdSINVsU9no3hPGeetp2phxi6Hd96bwNgxvGzlJy5dnt16vbd2V07dTT6FI5kDfR0ZgNnU9T3_mSvC3bfjLUBl8ml-Wxy6-s5Fj3vHiypj65F4d6Wtx9vPp-eb28-fLp8-WHm6WRTIxLVpmK2Eo6JZ2zogEpjDOGeAPVypraGrJg0DDDmF0zQ0wIU5Ox2SKMkvy0eL_PHabV1lnj_Bip10PsthR3OlCn_1V8d6_b8FML5LKSTQ44OwTE8GNyadTbLhnX9-RdmJLGBjg0nEn5MCqVULVSOfpBtKo4R4U1ZPTtf-gmTNHnpc2UyL8HYqYu9pSJIaXo1scREfR8F3q-C_3nLrLj9d-bOfK_DyED5QGYncc4RM1ZLk09T_xqj2zSGOKREUzl3rHK-pu9vqagqY1d0nffGGDuAQVnouK_AEVR0n0</recordid><startdate>20140812</startdate><enddate>20140812</enddate><creator>Kim, Jung Dae</creator><creator>Toda, Chitoku</creator><creator>D'Agostino, Giuseppe</creator><creator>Zeiss, Caroline J.</creator><creator>DiLeone, Ralph J.</creator><creator>Elsworth, John D.</creator><creator>Kibbey, Richard G.</creator><creator>Chan, Owen</creator><creator>Harvey, Brandon K.</creator><creator>Richie, Christopher T.</creator><creator>Savolainen, Mari</creator><creator>Myöhännen, Timo</creator><creator>Jeong, Jin Kwon</creator><creator>Diano, Sabrina</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20140812</creationdate><title>Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice</title><author>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 ; Myöhännen, Timo ; Jeong, Jin Kwon ; Diano, Sabrina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c624t-25c5a2b6e96eed48064cecca3805bdc7dcad0c1c2c22df2ca244c7acdb6e4c963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>autonomic nervous system</topic><topic>Biological Sciences</topic><topic>Blood Glucose - metabolism</topic><topic>Brain</topic><topic>Fasting</topic><topic>Gene Expression</topic><topic>Gene expression regulation</topic><topic>Gene Knockdown Techniques</topic><topic>Genotype & phenotype</topic><topic>glucagon</topic><topic>Glucagon - metabolism</topic><topic>Glucose</topic><topic>Glucose Clamp Technique</topic><topic>Glucose Intolerance - enzymology</topic><topic>Glucose Intolerance - etiology</topic><topic>glucose tolerance</topic><topic>Glucose tolerance test</topic><topic>Hypothalamic regulation</topic><topic>Hypothalamus</topic><topic>Hypothalamus - enzymology</topic><topic>Hypothalamus - physiology</topic><topic>Indoles - pharmacology</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Ion Channels - genetics</topic><topic>islets of Langerhans</topic><topic>Male</topic><topic>mechanism of action</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mode of action</topic><topic>Nervous system</topic><topic>norepinephrine</topic><topic>Pancreas</topic><topic>Pancreas - metabolism</topic><topic>phenotype</topic><topic>Phosphorylation</topic><topic>propranolol</topic><topic>Receptor, Insulin - metabolism</topic><topic>Receptors</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>Rodents</topic><topic>Serine Endopeptidases - deficiency</topic><topic>Serine Endopeptidases - genetics</topic><topic>Serine Endopeptidases - metabolism</topic><topic>Serine Proteinase Inhibitors - pharmacology</topic><topic>Thiazolidines - pharmacology</topic><topic>Uncoupling Protein 1</topic><topic>Ventromedial Hypothalamic Nucleus - enzymology</topic><topic>Ventromedial Hypothalamic Nucleus - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Jung Dae</creatorcontrib><creatorcontrib>Toda, Chitoku</creatorcontrib><creatorcontrib>D'Agostino, Giuseppe</creatorcontrib><creatorcontrib>Zeiss, Caroline J.</creatorcontrib><creatorcontrib>DiLeone, Ralph J.</creatorcontrib><creatorcontrib>Elsworth, John D.</creatorcontrib><creatorcontrib>Kibbey, Richard G.</creatorcontrib><creatorcontrib>Chan, Owen</creatorcontrib><creatorcontrib>Harvey, Brandon K.</creatorcontrib><creatorcontrib>Richie, Christopher T.</creatorcontrib><creatorcontrib>Savolainen, Mari</creatorcontrib><creatorcontrib>Myöhännen, Timo</creatorcontrib><creatorcontrib>Jeong, Jin Kwon</creatorcontrib><creatorcontrib>Diano, Sabrina</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Jung Dae</au><au>Toda, Chitoku</au><au>D'Agostino, Giuseppe</au><au>Zeiss, Caroline J.</au><au>DiLeone, Ralph J.</au><au>Elsworth, John D.</au><au>Kibbey, Richard G.</au><au>Chan, Owen</au><au>Harvey, Brandon K.</au><au>Richie, Christopher T.</au><au>Savolainen, Mari</au><au>Myöhännen, Timo</au><au>Jeong, Jin Kwon</au><au>Diano, Sabrina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2014-08-12</date><risdate>2014</risdate><volume>111</volume><issue>32</issue><spage>11876</spage><epage>11881</epage><pages>11876-11881</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>25071172</pmid><doi>10.1073/pnas.1406000111</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals autonomic nervous system Biological Sciences Blood Glucose - metabolism Brain Fasting Gene Expression Gene expression regulation Gene Knockdown Techniques Genotype & phenotype glucagon Glucagon - metabolism Glucose Glucose Clamp Technique Glucose Intolerance - enzymology Glucose Intolerance - etiology glucose tolerance Glucose tolerance test Hypothalamic regulation Hypothalamus Hypothalamus - enzymology Hypothalamus - physiology Indoles - pharmacology Insulin Insulin - metabolism Insulin Secretion Ion Channels - genetics islets of Langerhans Male mechanism of action Messenger RNA Mice Mice, Transgenic Mitochondrial Proteins - genetics Mode of action Nervous system norepinephrine Pancreas Pancreas - metabolism phenotype Phosphorylation propranolol Receptor, Insulin - metabolism Receptors Recombinant Proteins - genetics Recombinant Proteins - metabolism Rodents 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 |
| title | Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice |
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