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The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here,...
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| Published in: | The Journal of clinical investigation 2014-10, Vol.124 (10), p.4473-4488 |
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| creator | Secher, Anna Jelsing, Jacob Baquero, Arian F Hecksher-Sørensen, Jacob Cowley, Michael A Dalbøge, Louise S Hansen, Gitte Grove, Kevin L Pyke, Charles Raun, Kirsten Schäffer, Lauge Tang-Christensen, Mads Verma, Saurabh Witgen, Brent M Vrang, Niels Bjerre Knudsen, Lotte |
| description | Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss. |
| doi_str_mv | 10.1172/JCI75276 |
| format | article |
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Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI75276</identifier><identifier>PMID: 25202980</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Arcuate Nucleus of Hypothalamus - drug effects ; Biomedical research ; Body Weight - drug effects ; Disease Models, Animal ; Electrophysiology ; Food ; Glucagon-Like Peptide 1 - analogs & derivatives ; Glucagon-Like Peptide 1 - pharmacology ; Glucagon-Like Peptide-1 Receptor ; Hypothalamus ; Hypothalamus - metabolism ; Liraglutide ; Male ; Medical examination ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins - metabolism ; Neural circuitry ; Neurons - metabolism ; Obesity ; Observations ; Paraventricular Hypothalamic Nucleus - metabolism ; Patient outcomes ; Peptides ; Physiological aspects ; Physiology ; Pro-Opiomelanocortin - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucagon - metabolism ; Rodents ; Software ; Vagus Nerve - metabolism ; Weight control ; Weight loss ; Weight Loss - drug effects</subject><ispartof>The Journal of clinical investigation, 2014-10, Vol.124 (10), p.4473-4488</ispartof><rights>COPYRIGHT 2014 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Oct 2014</rights><rights>Copyright © 2014, American Society for Clinical Investigation 2014 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c676t-bf92092730e3ebf4cb6f7ed72e0ffc9ed8dfb41b8fc069bb855541d0919e26053</citedby><cites>FETCH-LOGICAL-c676t-bf92092730e3ebf4cb6f7ed72e0ffc9ed8dfb41b8fc069bb855541d0919e26053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215190/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215190/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25202980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Secher, Anna</creatorcontrib><creatorcontrib>Jelsing, Jacob</creatorcontrib><creatorcontrib>Baquero, Arian F</creatorcontrib><creatorcontrib>Hecksher-Sørensen, Jacob</creatorcontrib><creatorcontrib>Cowley, Michael A</creatorcontrib><creatorcontrib>Dalbøge, Louise S</creatorcontrib><creatorcontrib>Hansen, Gitte</creatorcontrib><creatorcontrib>Grove, Kevin L</creatorcontrib><creatorcontrib>Pyke, Charles</creatorcontrib><creatorcontrib>Raun, Kirsten</creatorcontrib><creatorcontrib>Schäffer, Lauge</creatorcontrib><creatorcontrib>Tang-Christensen, Mads</creatorcontrib><creatorcontrib>Verma, Saurabh</creatorcontrib><creatorcontrib>Witgen, Brent M</creatorcontrib><creatorcontrib>Vrang, Niels</creatorcontrib><creatorcontrib>Bjerre Knudsen, Lotte</creatorcontrib><title>The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.</description><subject>Animals</subject><subject>Arcuate Nucleus of Hypothalamus - drug effects</subject><subject>Biomedical research</subject><subject>Body Weight - drug effects</subject><subject>Disease Models, Animal</subject><subject>Electrophysiology</subject><subject>Food</subject><subject>Glucagon-Like Peptide 1 - analogs & derivatives</subject><subject>Glucagon-Like Peptide 1 - pharmacology</subject><subject>Glucagon-Like Peptide-1 Receptor</subject><subject>Hypothalamus</subject><subject>Hypothalamus - metabolism</subject><subject>Liraglutide</subject><subject>Male</subject><subject>Medical examination</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neural circuitry</subject><subject>Neurons - metabolism</subject><subject>Obesity</subject><subject>Observations</subject><subject>Paraventricular Hypothalamic Nucleus - metabolism</subject><subject>Patient outcomes</subject><subject>Peptides</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Pro-Opiomelanocortin - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Glucagon - metabolism</subject><subject>Rodents</subject><subject>Software</subject><subject>Vagus Nerve - metabolism</subject><subject>Weight control</subject><subject>Weight loss</subject><subject>Weight Loss - drug effects</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqNkk1v1DAQhiMEotuCxC9AkZBQOaTYThzbF6RqBWXRSkXQcrUcZ5y4ytqLnfDx7_GKbWnQHiofLHueeT3jebPsBUZnGDPy9tNyxShh9aNsgSnlBSclf5wtECK4EKzkR9lxjDcI4aqi1dPsiFCCiOBokV1f9ZCroCc1Qu4mPcAU8w20Np1jfrH-XOA8gIbt6EOuOu9sHPPBBtUN02hbKFrYgmvBjflPsF2fgj7GZ9kTo4YIz_f7SXb94f3V8mOxvrxYLc_Xha5ZPRaNEQQJwkoEJTSm0k1tGLSMADJGC2h5a5oKN9xoVIum4ZTSCrdIYAGkRrQ8yd791d1OTSpapzKCGuQ22I0Kv6VXVs4jzvay8z9kRTDFAiWB071A8N8niKPc2KhhGJQDP0WJa5IeYrR8AEp5jYRIogl99R9646fg0k8kQVxizCnD_6hODSCtMz6VqHei8rzkVAiemk1UcYDqwEHqxzswNl3P-LMDfFotbKw-mPBmlpCYEX6NnZpilKuvXx7OXn6bs6_vsT2oYeyj37nGuzgH9x-rQ7JOAHM3P4zkzt7y1t4JfXl_3nfgrZ_LP7UI8Js</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Secher, Anna</creator><creator>Jelsing, Jacob</creator><creator>Baquero, Arian F</creator><creator>Hecksher-Sørensen, Jacob</creator><creator>Cowley, Michael A</creator><creator>Dalbøge, Louise S</creator><creator>Hansen, Gitte</creator><creator>Grove, Kevin L</creator><creator>Pyke, Charles</creator><creator>Raun, Kirsten</creator><creator>Schäffer, Lauge</creator><creator>Tang-Christensen, Mads</creator><creator>Verma, Saurabh</creator><creator>Witgen, Brent M</creator><creator>Vrang, Niels</creator><creator>Bjerre Knudsen, Lotte</creator><general>American Society for Clinical Investigation</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20141001</creationdate><title>The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss</title><author>Secher, Anna ; Jelsing, Jacob ; Baquero, Arian F ; Hecksher-Sørensen, Jacob ; Cowley, Michael A ; Dalbøge, Louise S ; Hansen, Gitte ; Grove, Kevin L ; Pyke, Charles ; Raun, Kirsten ; Schäffer, Lauge ; Tang-Christensen, Mads ; Verma, Saurabh ; Witgen, Brent M ; Vrang, Niels ; Bjerre Knudsen, Lotte</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c676t-bf92092730e3ebf4cb6f7ed72e0ffc9ed8dfb41b8fc069bb855541d0919e26053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Arcuate Nucleus of Hypothalamus - 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Niels Vrang and Lotte Bjerre Knudsen are co–senior authors.</notes><abstract>Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>25202980</pmid><doi>10.1172/JCI75276</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2014-10, Vol.124 (10), p.4473-4488 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4215190 |
| source | PubMed Central (Open access); EZB Electronic Journals Library |
| subjects | Animals Arcuate Nucleus of Hypothalamus - drug effects Biomedical research Body Weight - drug effects Disease Models, Animal Electrophysiology Food Glucagon-Like Peptide 1 - analogs & derivatives Glucagon-Like Peptide 1 - pharmacology Glucagon-Like Peptide-1 Receptor Hypothalamus Hypothalamus - metabolism Liraglutide Male Medical examination Mice Mice, Transgenic Nerve Tissue Proteins - metabolism Neural circuitry Neurons - metabolism Obesity Observations Paraventricular Hypothalamic Nucleus - metabolism Patient outcomes Peptides Physiological aspects Physiology Pro-Opiomelanocortin - metabolism Rats Rats, Sprague-Dawley Receptors, Glucagon - metabolism Rodents Software Vagus Nerve - metabolism Weight control Weight loss Weight Loss - drug effects |
| title | The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T14%3A01%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20arcuate%20nucleus%20mediates%20GLP-1%20receptor%20agonist%20liraglutide-dependent%20weight%20loss&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Secher,%20Anna&rft.date=2014-10-01&rft.volume=124&rft.issue=10&rft.spage=4473&rft.epage=4488&rft.pages=4473-4488&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI75276&rft_dat=%3Cgale_pubme%3EA385998541%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c676t-bf92092730e3ebf4cb6f7ed72e0ffc9ed8dfb41b8fc069bb855541d0919e26053%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1613118571&rft_id=info:pmid/25202980&rft_galeid=A385998541&rfr_iscdi=true |