A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change
Bombesin receptor subtype 3 (BRS-3) is an orphan G protein–coupled receptor. Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effect...
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| creator | Nio, Yasunori Hotta, Natsu Maruyama, Minoru Hamagami, Kenichi Nagi, Toshimi Funata, Masaaki Sakamoto, Junichi Nakakariya, Masanori Amano, Nobuyuki Okawa, Tomohiro Arikawa, Yasuyoshi Sasaki, Shinobu Okuda, Shoki Kasai, Shizuo Habata, Yugo Nagisa, Yasutaka |
| description | Bombesin receptor subtype 3 (BRS-3) is an orphan G protein–coupled receptor. Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced–obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic–pituitary–adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.We identified a novel BRS-3 agonist, compound-A, and possible mechanism of antiobesity effects modulating circadian rhythm and activation of the HPA axis via SCN. |
| doi_str_mv | 10.1210/en.2016-1825 |
| format | Article |
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Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced–obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic–pituitary–adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.We identified a novel BRS-3 agonist, compound-A, and possible mechanism of antiobesity effects modulating circadian rhythm and activation of the HPA axis via SCN.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2016-1825</identifier><identifier>PMID: 28324017</identifier><language>eng</language><publisher>Washington, DC: Endocrine Society</publisher><subject>Activation ; Agonists ; Animal tissues ; Animals ; Anti-Obesity Agents - pharmacology ; Blood levels ; Blood pressure ; Body weight ; Body Weight - drug effects ; Body weight loss ; Bombesin ; c-Fos protein ; Circadian rhythm ; Circadian Rhythm - drug effects ; Circadian rhythms ; Control centres ; Corticosterone ; Corticosterone - blood ; Diet ; Diet, High-Fat ; Endocrinology ; Energy expenditure ; Energy metabolism ; Energy Metabolism - drug effects ; Gene expression ; Hypothalamic-pituitary-adrenal axis ; Hypothalamo-Hypophyseal System - drug effects ; Hypothalamo-Hypophyseal System - metabolism ; Hypothalamus ; Lipid metabolism ; Lipid Metabolism - drug effects ; Lipids ; Male ; Males ; Metabolism ; Nervous system ; Obesity ; Obesity - drug therapy ; Obesity - metabolism ; Obesity - physiopathology ; Oral administration ; Phenotypes ; Pituitary ; Pituitary-Adrenal System - drug effects ; Pituitary-Adrenal System - metabolism ; Pressure effects ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Receptors ; Receptors, Bombesin - agonists ; Ribonucleic acid ; RNA ; Rodents ; Side effects ; Stimulation ; Suprachiasmatic nucleus ; Sympathetic nervous system ; Weight loss ; Weight Loss - drug effects ; Weight reduction</subject><ispartof>Endocrinology (Philadelphia), 2017-05, Vol.158 (5), p.1298-1313</ispartof><rights>Copyright © 2017 Endocrine Society 2017</rights><rights>Copyright © 2017 Endocrine Society.</rights><rights>Copyright © 2017 Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-669a94449d8e1caabe30835290444acfd9e1dc1894018dbb6b44311e11b7fe3c3</citedby><cites>FETCH-LOGICAL-c417t-669a94449d8e1caabe30835290444acfd9e1dc1894018dbb6b44311e11b7fe3c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28324017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nio, Yasunori</creatorcontrib><creatorcontrib>Hotta, Natsu</creatorcontrib><creatorcontrib>Maruyama, Minoru</creatorcontrib><creatorcontrib>Hamagami, Kenichi</creatorcontrib><creatorcontrib>Nagi, Toshimi</creatorcontrib><creatorcontrib>Funata, Masaaki</creatorcontrib><creatorcontrib>Sakamoto, Junichi</creatorcontrib><creatorcontrib>Nakakariya, Masanori</creatorcontrib><creatorcontrib>Amano, Nobuyuki</creatorcontrib><creatorcontrib>Okawa, Tomohiro</creatorcontrib><creatorcontrib>Arikawa, Yasuyoshi</creatorcontrib><creatorcontrib>Sasaki, Shinobu</creatorcontrib><creatorcontrib>Okuda, Shoki</creatorcontrib><creatorcontrib>Kasai, Shizuo</creatorcontrib><creatorcontrib>Habata, Yugo</creatorcontrib><creatorcontrib>Nagisa, Yasutaka</creatorcontrib><title>A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Bombesin receptor subtype 3 (BRS-3) is an orphan G protein–coupled receptor. Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced–obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic–pituitary–adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.We identified a novel BRS-3 agonist, compound-A, and possible mechanism of antiobesity effects modulating circadian rhythm and activation of the HPA axis via SCN.</description><subject>Activation</subject><subject>Agonists</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Anti-Obesity Agents - pharmacology</subject><subject>Blood levels</subject><subject>Blood pressure</subject><subject>Body weight</subject><subject>Body Weight - drug effects</subject><subject>Body weight loss</subject><subject>Bombesin</subject><subject>c-Fos protein</subject><subject>Circadian rhythm</subject><subject>Circadian Rhythm - drug effects</subject><subject>Circadian rhythms</subject><subject>Control centres</subject><subject>Corticosterone</subject><subject>Corticosterone - blood</subject><subject>Diet</subject><subject>Diet, High-Fat</subject><subject>Endocrinology</subject><subject>Energy expenditure</subject><subject>Energy metabolism</subject><subject>Energy Metabolism - drug effects</subject><subject>Gene expression</subject><subject>Hypothalamic-pituitary-adrenal axis</subject><subject>Hypothalamo-Hypophyseal System - drug effects</subject><subject>Hypothalamo-Hypophyseal System - metabolism</subject><subject>Hypothalamus</subject><subject>Lipid metabolism</subject><subject>Lipid Metabolism - drug effects</subject><subject>Lipids</subject><subject>Male</subject><subject>Males</subject><subject>Metabolism</subject><subject>Nervous system</subject><subject>Obesity</subject><subject>Obesity - drug therapy</subject><subject>Obesity - metabolism</subject><subject>Obesity - physiopathology</subject><subject>Oral administration</subject><subject>Phenotypes</subject><subject>Pituitary</subject><subject>Pituitary-Adrenal System - drug effects</subject><subject>Pituitary-Adrenal System - metabolism</subject><subject>Pressure effects</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors</subject><subject>Receptors, Bombesin - agonists</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Rodents</subject><subject>Side effects</subject><subject>Stimulation</subject><subject>Suprachiasmatic nucleus</subject><subject>Sympathetic nervous system</subject><subject>Weight loss</subject><subject>Weight Loss - drug effects</subject><subject>Weight reduction</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ks-O0zAQxi0EYsvCjTOyxAEOZPHYbmIfS_m3UtGiXRDHyHGmjVdJHGwHqTckHoE35Elw6cIBCU6WrZ-_mW--IeQhsDPgwJ7jeMYZlAUovrxFFqDlsqigYrfJgjEQRcV5dULuxXidr1JKcZeccCW4ZFAtyLcVvcIebXJfkL7wQ4PRjfQSLU7JB3o1N2k_IRV0tfOji4m-D37wCSP9hG7XJbrxMdL85Z3pkb50mIrzsZ0ttj--fr_IakgvTcq0Sx1du2BN60wu0O1TN9B1Z8Yd3id3tqaP-ODmPCUfX7_6sH5bbC7enK9Xm8JKqFJRltrobEC3CsEa06BgSiy5ZvnR2G2rEVoLSmdnqm2asslmARCgqbYorDglT4-6U_CfZ4ypHly02PdmRD_HGpRiTMkKeEYf_4Ve-zmMubtagGB5vkLp_1GgS60lX8oyU8-OlA15VgG39RTcYMK-BlYfIqxxrA8R1ocIM_7oRnRuBmz_wL8zy8CTI-Dn6V9Sv7ZB_ATUkaGt</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Nio, Yasunori</creator><creator>Hotta, Natsu</creator><creator>Maruyama, Minoru</creator><creator>Hamagami, Kenichi</creator><creator>Nagi, Toshimi</creator><creator>Funata, Masaaki</creator><creator>Sakamoto, Junichi</creator><creator>Nakakariya, Masanori</creator><creator>Amano, Nobuyuki</creator><creator>Okawa, Tomohiro</creator><creator>Arikawa, Yasuyoshi</creator><creator>Sasaki, Shinobu</creator><creator>Okuda, Shoki</creator><creator>Kasai, Shizuo</creator><creator>Habata, Yugo</creator><creator>Nagisa, Yasutaka</creator><general>Endocrine Society</general><general>Oxford University Press</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>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20170501</creationdate><title>A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change</title><author>Nio, Yasunori ; Hotta, Natsu ; Maruyama, Minoru ; Hamagami, Kenichi ; Nagi, Toshimi ; Funata, Masaaki ; Sakamoto, Junichi ; Nakakariya, Masanori ; Amano, Nobuyuki ; Okawa, Tomohiro ; Arikawa, Yasuyoshi ; Sasaki, Shinobu ; Okuda, Shoki ; Kasai, Shizuo ; Habata, Yugo ; Nagisa, Yasutaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-669a94449d8e1caabe30835290444acfd9e1dc1894018dbb6b44311e11b7fe3c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>Agonists</topic><topic>Animal tissues</topic><topic>Animals</topic><topic>Anti-Obesity Agents - pharmacology</topic><topic>Blood levels</topic><topic>Blood pressure</topic><topic>Body weight</topic><topic>Body Weight - drug effects</topic><topic>Body weight loss</topic><topic>Bombesin</topic><topic>c-Fos protein</topic><topic>Circadian rhythm</topic><topic>Circadian Rhythm - drug effects</topic><topic>Circadian rhythms</topic><topic>Control centres</topic><topic>Corticosterone</topic><topic>Corticosterone - blood</topic><topic>Diet</topic><topic>Diet, High-Fat</topic><topic>Endocrinology</topic><topic>Energy expenditure</topic><topic>Energy metabolism</topic><topic>Energy Metabolism - drug effects</topic><topic>Gene expression</topic><topic>Hypothalamic-pituitary-adrenal axis</topic><topic>Hypothalamo-Hypophyseal System - drug effects</topic><topic>Hypothalamo-Hypophyseal System - metabolism</topic><topic>Hypothalamus</topic><topic>Lipid metabolism</topic><topic>Lipid Metabolism - drug effects</topic><topic>Lipids</topic><topic>Male</topic><topic>Males</topic><topic>Metabolism</topic><topic>Nervous system</topic><topic>Obesity</topic><topic>Obesity - 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Academic</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nio, Yasunori</au><au>Hotta, Natsu</au><au>Maruyama, Minoru</au><au>Hamagami, Kenichi</au><au>Nagi, Toshimi</au><au>Funata, Masaaki</au><au>Sakamoto, Junichi</au><au>Nakakariya, Masanori</au><au>Amano, Nobuyuki</au><au>Okawa, Tomohiro</au><au>Arikawa, Yasuyoshi</au><au>Sasaki, Shinobu</au><au>Okuda, Shoki</au><au>Kasai, Shizuo</au><au>Habata, Yugo</au><au>Nagisa, Yasutaka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>158</volume><issue>5</issue><spage>1298</spage><epage>1313</epage><pages>1298-1313</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><abstract>Bombesin receptor subtype 3 (BRS-3) is an orphan G protein–coupled receptor. Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced–obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic–pituitary–adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.We identified a novel BRS-3 agonist, compound-A, and possible mechanism of antiobesity effects modulating circadian rhythm and activation of the HPA axis via SCN.</abstract><cop>Washington, DC</cop><pub>Endocrine Society</pub><pmid>28324017</pmid><doi>10.1210/en.2016-1825</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0013-7227 |
| ispartof | Endocrinology (Philadelphia), 2017-05, Vol.158 (5), p.1298-1313 |
| issn | 0013-7227 1945-7170 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1880084712 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Activation Agonists Animal tissues Animals Anti-Obesity Agents - pharmacology Blood levels Blood pressure Body weight Body Weight - drug effects Body weight loss Bombesin c-Fos protein Circadian rhythm Circadian Rhythm - drug effects Circadian rhythms Control centres Corticosterone Corticosterone - blood Diet Diet, High-Fat Endocrinology Energy expenditure Energy metabolism Energy Metabolism - drug effects Gene expression Hypothalamic-pituitary-adrenal axis Hypothalamo-Hypophyseal System - drug effects Hypothalamo-Hypophyseal System - metabolism Hypothalamus Lipid metabolism Lipid Metabolism - drug effects Lipids Male Males Metabolism Nervous system Obesity Obesity - drug therapy Obesity - metabolism Obesity - physiopathology Oral administration Phenotypes Pituitary Pituitary-Adrenal System - drug effects Pituitary-Adrenal System - metabolism Pressure effects Rats Rats, Inbred F344 Rats, Sprague-Dawley Receptors Receptors, Bombesin - agonists Ribonucleic acid RNA Rodents Side effects Stimulation Suprachiasmatic nucleus Sympathetic nervous system Weight loss Weight Loss - drug effects Weight reduction |
| title | A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T06%3A06%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Selective%20Bombesin%20Receptor%20Subtype%203%20Agonist%20Promotes%20Weight%20Loss%20in%20Male%20Diet-Induced%E2%80%93Obese%20Rats%20With%20Circadian%20Rhythm%20Change&rft.jtitle=Endocrinology%20(Philadelphia)&rft.au=Nio,%20Yasunori&rft.date=2017-05-01&rft.volume=158&rft.issue=5&rft.spage=1298&rft.epage=1313&rft.pages=1298-1313&rft.issn=0013-7227&rft.eissn=1945-7170&rft_id=info:doi/10.1210/en.2016-1825&rft_dat=%3Cproquest_cross%3E1969942546%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1969942546&rft_id=info:pmid/28324017&rft_oup_id=10.1210/en.2016-1825&rfr_iscdi=true |