Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean
Members of the muscarinic acetylcholine receptor family (M1–M5) have central roles in the regulation of many fundamental physiological functions 1 , 2 . Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest,...
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| Veröffentlicht in: | Nature (London) 2001-03, Vol.410 (6825), p.207-212 |
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| creator | Yamada, Masahisa Miyakawa, Tsuyoshi Duttaroy, Alokesh Yamanaka, Akihiro Moriguchi, Toru Makita, Ryosuke Ogawa, Masaharu Chou, Chieh J. Xia, Bing Crawley, Jacqueline N. Felder, Christian C. Deng, Chu-Xia Wess, Jürgen |
| description | Members of the muscarinic acetylcholine receptor family (M1–M5) have central roles in the regulation of many fundamental physiological functions
1
,
2
. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands
3
. Here we show that mice deficient in the M3 muscarinic receptor (
M3R
-/-
mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake
4
,
5
, are significantly reduced in
M3R
-/-
mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in
M3R
-/-
mice. However,
M3R
-/-
mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system. |
| doi_str_mv | 10.1038/35065604 |
| format | Article |
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1
,
2
. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands
3
. Here we show that mice deficient in the M3 muscarinic receptor (
M3R
-/-
mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake
4
,
5
, are significantly reduced in
M3R
-/-
mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in
M3R
-/-
mice. However,
M3R
-/-
mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/35065604</identifier><identifier>PMID: 11242080</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Appetite Regulation - physiology ; Biological and medical sciences ; Body fat ; Body Weight ; Eating ; Feeding and Eating Disorders - etiology ; Feeding Behavior - physiology ; Feeding. Feeding behavior ; Female ; Food ; Fundamental and applied biological sciences. Psychology ; Gene Targeting ; Genetics ; Glucose Tolerance Test ; Hormones - blood ; Humanities and Social Sciences ; Insulin ; Insulin - blood ; Leptin - blood ; letter ; Locomotion ; Male ; Metabolism ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Mutation ; Neuropeptides - physiology ; Obesity ; Oxygen Consumption ; Receptor, Muscarinic M3 ; Receptors, Muscarinic - deficiency ; Receptors, Muscarinic - genetics ; Receptors, Muscarinic - physiology ; Rodents ; Science ; Science (multidisciplinary) ; Thinness ; Triglycerides - blood ; Vertebrates: anatomy and physiology, studies on body, several organs or systems</subject><ispartof>Nature (London), 2001-03, Vol.410 (6825), p.207-212</ispartof><rights>Macmillan Magazines Ltd. 2001</rights><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2001 Nature Publishing Group</rights><rights>Copyright Macmillan Journals Ltd. Mar 8, 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c703t-a8da6e1f0b108ffdec7300cc2875438388fe19d770bbc708ff1d858d0b29618b3</citedby><cites>FETCH-LOGICAL-c703t-a8da6e1f0b108ffdec7300cc2875438388fe19d770bbc708ff1d858d0b29618b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/35065604$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/35065604$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=924191$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11242080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamada, Masahisa</creatorcontrib><creatorcontrib>Miyakawa, Tsuyoshi</creatorcontrib><creatorcontrib>Duttaroy, Alokesh</creatorcontrib><creatorcontrib>Yamanaka, Akihiro</creatorcontrib><creatorcontrib>Moriguchi, Toru</creatorcontrib><creatorcontrib>Makita, Ryosuke</creatorcontrib><creatorcontrib>Ogawa, Masaharu</creatorcontrib><creatorcontrib>Chou, Chieh J.</creatorcontrib><creatorcontrib>Xia, Bing</creatorcontrib><creatorcontrib>Crawley, Jacqueline N.</creatorcontrib><creatorcontrib>Felder, Christian C.</creatorcontrib><creatorcontrib>Deng, Chu-Xia</creatorcontrib><creatorcontrib>Wess, Jürgen</creatorcontrib><title>Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Members of the muscarinic acetylcholine receptor family (M1–M5) have central roles in the regulation of many fundamental physiological functions
1
,
2
. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands
3
. Here we show that mice deficient in the M3 muscarinic receptor (
M3R
-/-
mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake
4
,
5
, are significantly reduced in
M3R
-/-
mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in
M3R
-/-
mice. However,
M3R
-/-
mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.</description><subject>Animals</subject><subject>Appetite Regulation - physiology</subject><subject>Biological and medical sciences</subject><subject>Body fat</subject><subject>Body Weight</subject><subject>Eating</subject><subject>Feeding and Eating Disorders - etiology</subject><subject>Feeding Behavior - physiology</subject><subject>Feeding. Feeding behavior</subject><subject>Female</subject><subject>Food</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Targeting</subject><subject>Genetics</subject><subject>Glucose Tolerance Test</subject><subject>Hormones - blood</subject><subject>Humanities and Social Sciences</subject><subject>Insulin</subject><subject>Insulin - blood</subject><subject>Leptin - blood</subject><subject>letter</subject><subject>Locomotion</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Neuropeptides - physiology</subject><subject>Obesity</subject><subject>Oxygen Consumption</subject><subject>Receptor, Muscarinic M3</subject><subject>Receptors, Muscarinic - deficiency</subject><subject>Receptors, Muscarinic - genetics</subject><subject>Receptors, Muscarinic - physiology</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Thinness</subject><subject>Triglycerides - blood</subject><subject>Vertebrates: anatomy and physiology, studies on body, several organs or systems</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0l2L1DAUBuAiijuugr9AioIfSNeTJmmSy2HwY2FHQVe8LGl62snaSbtJC86_N-uMjqOrSy4CyZNzyOFNkocETghQ-YpyKHgB7FYyI0wUGSukuJ3MAHKZgaTFUXIvhAsA4ESwu8kRITnLQcIsWS6twbTT5qt1bTquMF3SdD0Fo7111qTa4LjpzKrvrMPUo8Fh7H2qPaarzdAPK91eKVenHWp3P7nT6C7gg91-nHx-8_p88S47-_D2dDE_y4wAOmZa1rpA0kBFQDZNjUZQAGNyKTijkkrZIFG1EFBV8UUkpJZc1lDlqiCyosfJ023dwfeXE4axXNtgsOu0w34KpSgUZzxXET77P-SKEiEpvVkymgullLyxeaxHFGEQ4eM_4EU_eRcHU-bAmOL8B8q2qNUdltY1_ei1adGh113vsLHxeE6kBBCEsH3RA28Ge1n-jk6uQXHVuLbm2qovDh5EM-K3sdVTCOXpp4-H9uW_7fz8y-L9oX6-1cb3IXhsysHbtfabkkB5Fd7yZ3gjfbSb11Stsd7DXVojeLIDOga0a7x2xoZfTuUsDn7_lxAvXIt-P_a_Wn4HEMT7mQ</recordid><startdate>20010308</startdate><enddate>20010308</enddate><creator>Yamada, Masahisa</creator><creator>Miyakawa, Tsuyoshi</creator><creator>Duttaroy, Alokesh</creator><creator>Yamanaka, Akihiro</creator><creator>Moriguchi, Toru</creator><creator>Makita, Ryosuke</creator><creator>Ogawa, Masaharu</creator><creator>Chou, Chieh J.</creator><creator>Xia, Bing</creator><creator>Crawley, Jacqueline N.</creator><creator>Felder, Christian C.</creator><creator>Deng, Chu-Xia</creator><creator>Wess, Jürgen</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</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>ATWCN</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7SC</scope><scope>7SP</scope><scope>7SR</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>F28</scope><scope>JG9</scope><scope>JQ2</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>7X8</scope></search><sort><creationdate>20010308</creationdate><title>Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean</title><author>Yamada, Masahisa ; Miyakawa, Tsuyoshi ; Duttaroy, Alokesh ; Yamanaka, Akihiro ; Moriguchi, Toru ; Makita, Ryosuke ; Ogawa, Masaharu ; Chou, Chieh J. ; Xia, Bing ; Crawley, Jacqueline N. ; Felder, Christian C. ; Deng, Chu-Xia ; Wess, Jürgen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c703t-a8da6e1f0b108ffdec7300cc2875438388fe19d770bbc708ff1d858d0b29618b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Appetite Regulation - physiology</topic><topic>Biological and medical sciences</topic><topic>Body fat</topic><topic>Body Weight</topic><topic>Eating</topic><topic>Feeding and Eating Disorders - etiology</topic><topic>Feeding Behavior - physiology</topic><topic>Feeding. Feeding behavior</topic><topic>Female</topic><topic>Food</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Targeting</topic><topic>Genetics</topic><topic>Glucose Tolerance Test</topic><topic>Hormones - blood</topic><topic>Humanities and Social Sciences</topic><topic>Insulin</topic><topic>Insulin - blood</topic><topic>Leptin - blood</topic><topic>letter</topic><topic>Locomotion</topic><topic>Male</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Neuropeptides - physiology</topic><topic>Obesity</topic><topic>Oxygen Consumption</topic><topic>Receptor, Muscarinic M3</topic><topic>Receptors, Muscarinic - deficiency</topic><topic>Receptors, Muscarinic - genetics</topic><topic>Receptors, Muscarinic - physiology</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Thinness</topic><topic>Triglycerides - blood</topic><topic>Vertebrates: anatomy and physiology, studies on body, several organs or 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Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamada, Masahisa</au><au>Miyakawa, Tsuyoshi</au><au>Duttaroy, Alokesh</au><au>Yamanaka, Akihiro</au><au>Moriguchi, Toru</au><au>Makita, Ryosuke</au><au>Ogawa, Masaharu</au><au>Chou, Chieh J.</au><au>Xia, Bing</au><au>Crawley, Jacqueline N.</au><au>Felder, Christian C.</au><au>Deng, Chu-Xia</au><au>Wess, Jürgen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2001-03-08</date><risdate>2001</risdate><volume>410</volume><issue>6825</issue><spage>207</spage><epage>212</epage><pages>207-212</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Members of the muscarinic acetylcholine receptor family (M1–M5) have central roles in the regulation of many fundamental physiological functions
1
,
2
. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands
3
. Here we show that mice deficient in the M3 muscarinic receptor (
M3R
-/-
mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake
4
,
5
, are significantly reduced in
M3R
-/-
mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in
M3R
-/-
mice. However,
M3R
-/-
mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>11242080</pmid><doi>10.1038/35065604</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2001-03, Vol.410 (6825), p.207-212 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_76954529 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | Animals Appetite Regulation - physiology Biological and medical sciences Body fat Body Weight Eating Feeding and Eating Disorders - etiology Feeding Behavior - physiology Feeding. Feeding behavior Female Food Fundamental and applied biological sciences. Psychology Gene Targeting Genetics Glucose Tolerance Test Hormones - blood Humanities and Social Sciences Insulin Insulin - blood Leptin - blood letter Locomotion Male Metabolism Mice Mice, Inbred C57BL multidisciplinary Mutation Neuropeptides - physiology Obesity Oxygen Consumption Receptor, Muscarinic M3 Receptors, Muscarinic - deficiency Receptors, Muscarinic - genetics Receptors, Muscarinic - physiology Rodents Science Science (multidisciplinary) Thinness Triglycerides - blood Vertebrates: anatomy and physiology, studies on body, several organs or systems |
| title | Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T11%3A04%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mice%20lacking%20the%20M3%20muscarinic%20acetylcholine%20receptor%20are%20hypophagic%20and%20lean&rft.jtitle=Nature%20(London)&rft.au=Yamada,%20Masahisa&rft.date=2001-03-08&rft.volume=410&rft.issue=6825&rft.spage=207&rft.epage=212&rft.pages=207-212&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/35065604&rft_dat=%3Cgale_proqu%3EA188007114%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204495540&rft_id=info:pmid/11242080&rft_galeid=A188007114&rfr_iscdi=true |