Neonatal ghrelin programs development of hypothalamic feeding circuits
A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arc...
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| Veröffentlicht in: | The Journal of clinical investigation 2015-02, Vol.125 (2), p.846-858 |
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| creator | Steculorum, Sophie M Collden, Gustav Coupe, Berengere Croizier, Sophie Lockie, Sarah Andrews, Zane B Jarosch, Florian Klussmann, Sven Bouret, Sebastien G |
| description | A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation. |
| doi_str_mv | 10.1172/JCI73688 |
| format | Article |
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The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI73688</identifier><identifier>PMID: 25607843</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adipocytes - metabolism ; Adipocytes - pathology ; Animals ; Arcuate Nucleus of Hypothalamus - cytology ; Arcuate Nucleus of Hypothalamus - metabolism ; Axons - metabolism ; Biomedical research ; Feeding Behavior - physiology ; Food and nutrition ; Ghrelin ; Ghrelin - genetics ; Ghrelin - metabolism ; Hypotheses ; Infants (Newborn) ; Leptin - genetics ; Leptin - metabolism ; Metabolic disorders ; Mice ; Mice, Knockout ; Neural circuitry ; Nutrition ; Obesity ; Physiological aspects ; Physiology ; Properties ; Rodents ; Signal Transduction - physiology ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Weight control</subject><ispartof>The Journal of clinical investigation, 2015-02, Vol.125 (2), p.846-858</ispartof><rights>COPYRIGHT 2015 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Feb 2015</rights><rights>Copyright © 2015, American Society for Clinical Investigation 2015 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c530t-447b32b9e0f346a3ea15ec470ab0034044d7dd66f528dfa018a3dfeb1b721b6a3</citedby><cites>FETCH-LOGICAL-c530t-447b32b9e0f346a3ea15ec470ab0034044d7dd66f528dfa018a3dfeb1b721b6a3</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/PMC4319433/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319433/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25607843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Steculorum, Sophie M</creatorcontrib><creatorcontrib>Collden, Gustav</creatorcontrib><creatorcontrib>Coupe, Berengere</creatorcontrib><creatorcontrib>Croizier, Sophie</creatorcontrib><creatorcontrib>Lockie, Sarah</creatorcontrib><creatorcontrib>Andrews, Zane B</creatorcontrib><creatorcontrib>Jarosch, Florian</creatorcontrib><creatorcontrib>Klussmann, Sven</creatorcontrib><creatorcontrib>Bouret, Sebastien G</creatorcontrib><title>Neonatal ghrelin programs development of hypothalamic feeding circuits</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.</description><subject>Adipocytes - metabolism</subject><subject>Adipocytes - pathology</subject><subject>Animals</subject><subject>Arcuate Nucleus of Hypothalamus - cytology</subject><subject>Arcuate Nucleus of Hypothalamus - metabolism</subject><subject>Axons - metabolism</subject><subject>Biomedical research</subject><subject>Feeding Behavior - physiology</subject><subject>Food and nutrition</subject><subject>Ghrelin</subject><subject>Ghrelin - genetics</subject><subject>Ghrelin - metabolism</subject><subject>Hypotheses</subject><subject>Infants (Newborn)</subject><subject>Leptin - genetics</subject><subject>Leptin - metabolism</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neural circuitry</subject><subject>Nutrition</subject><subject>Obesity</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Properties</subject><subject>Rodents</subject><subject>Signal Transduction - physiology</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Weight control</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkctu1TAURS0EopeCxBegSEiISejx25kgVVcUiio6gbHlJCeJKycOdlKpf0-u-oAy6ugMvLx8vDchbyl8olSzk-_7c82VMc_IjkppSsO4eU52AIyWlebmiLzK-QqACiHFS3LEpAJtBN-Rsx8YJ7e4UPRDwuCnYk6xT27MRYvXGOI84rQUsSuGmzkugwtu9E3RIbZ-6ovGp2b1S35NXnQuZHxzN4_Jr7MvP_ffyovLr-f704uykRyWUghdc1ZXCB0XynF0VGIjNLgagAsQotVtq1QnmWk7B9Q43nZY01ozWm8XjsnnW--81iO2zbZbcsHOyY8u3djovH18MvnB9vHaCk4rwfkm-HgnSPH3inmxo88NhuAmjGu2VCnDhFIMnoDKjQRayQ19_x96Fdc0bUkchFQBr8xB-OGW6l1AO6ALy5BjWBcfp2xPBVCtNRPm78tNijkn7B4-SMEeCrf3hW_ou38DeQDvG-Z_AP1DpQk</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Steculorum, Sophie M</creator><creator>Collden, Gustav</creator><creator>Coupe, Berengere</creator><creator>Croizier, Sophie</creator><creator>Lockie, Sarah</creator><creator>Andrews, Zane B</creator><creator>Jarosch, Florian</creator><creator>Klussmann, Sven</creator><creator>Bouret, Sebastien G</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>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>7TK</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150201</creationdate><title>Neonatal ghrelin programs development of hypothalamic feeding circuits</title><author>Steculorum, Sophie M ; Collden, Gustav ; Coupe, Berengere ; Croizier, Sophie ; Lockie, Sarah ; Andrews, Zane B ; Jarosch, Florian ; Klussmann, Sven ; Bouret, Sebastien G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c530t-447b32b9e0f346a3ea15ec470ab0034044d7dd66f528dfa018a3dfeb1b721b6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adipocytes - 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Academic</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Steculorum, Sophie M</au><au>Collden, Gustav</au><au>Coupe, Berengere</au><au>Croizier, Sophie</au><au>Lockie, Sarah</au><au>Andrews, Zane B</au><au>Jarosch, Florian</au><au>Klussmann, Sven</au><au>Bouret, Sebastien G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neonatal ghrelin programs development of hypothalamic feeding circuits</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>125</volume><issue>2</issue><spage>846</spage><epage>858</epage><pages>846-858</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>25607843</pmid><doi>10.1172/JCI73688</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adipocytes - metabolism Adipocytes - pathology Animals Arcuate Nucleus of Hypothalamus - cytology Arcuate Nucleus of Hypothalamus - metabolism Axons - metabolism Biomedical research Feeding Behavior - physiology Food and nutrition Ghrelin Ghrelin - genetics Ghrelin - metabolism Hypotheses Infants (Newborn) Leptin - genetics Leptin - metabolism Metabolic disorders Mice Mice, Knockout Neural circuitry Nutrition Obesity Physiological aspects Physiology Properties Rodents Signal Transduction - physiology STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Weight control |
| title | Neonatal ghrelin programs development of hypothalamic feeding circuits |
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