{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:18:59Z","timestamp":1773155939880,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,9,10]],"date-time":"2012-09-10T00:00:00Z","timestamp":1347235200000},"content-version":"vor","delay-in-days":193,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Obesity"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:p>Obesity is caused by an imbalance between energy intake and expenditure and has become a major health\u2010care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional <jats:italic>Mc4r<\/jats:italic> knockout model in the rat, resulting from an <jats:italic>N<\/jats:italic>\u2010ethyl\u2010<jats:italic>N<\/jats:italic>\u2010nitrosourea mutagenesis\u2013induced point mutation. <jats:italic>In vitro<\/jats:italic> observations revealed impaired membrane\u2010binding and subsequent nonfunctionality of the receptor, whereas <jats:italic>in vivo<\/jats:italic> observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti\u2010Related Protein<jats:sub>79\u2013129<\/jats:sub> (AgRP<jats:sub>79\u2013129<\/jats:sub>), an MC4R inverse agonist, or Melanotan\u2010II (MTII), an MC4R agonist, did affect feeding behavior in wild\u2010type rats but not in homozygous mutant rats, confirming complete loss of MC4R function <jats:italic>in vivo<\/jats:italic>. Finally, ICV administration of MTII induced excessive grooming behavior in wild\u2010type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII\u2010induced grooming behavior is exclusively regulated <jats:italic>via<\/jats:italic> MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function.<\/jats:p>","DOI":"10.1038\/oby.2011.81","type":"journal-article","created":{"date-parts":[[2011,4,28]],"date-time":"2011-04-28T12:29:35Z","timestamp":1303993775000},"page":"612-621","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Melanocortin Receptor 4 Deficiency Affects Body Weight Regulation, Grooming Behavior, and Substrate Preference in the Rat"],"prefix":"10.1002","volume":"20","author":[{"given":"Joram D.","family":"Mul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"van Boxtel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan J.M.","family":"Bergen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike A.D.","family":"Brans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan H.","family":"Brakkee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pim W.","family":"Toonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith M.","family":"Garner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger A.H.","family":"Adan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin","family":"Cuppen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,9,10]]},"reference":[{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/371799a0"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5335.135"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/35007534"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0037"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1455"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9238"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9397"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn431"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1411"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.140"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.301"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.287"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000916"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81865-6"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa022050"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021971"},{"key":"e_1_2_8_18_2","article-title":"Systematic generation of in vivo G protein\u2010coupled receptor mutants in the rat","author":"Boxtel R.","year":"2010","journal-title":"Pharmacogenomics J"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211546200"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00018a005"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00154.2009"},{"key":"e_1_2_8_22_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/01.fpc.0000184960.82903.8f","article-title":"Generation of gene knockouts and mutant models in the laboratory rat by ENU\u2010driven target\u2010selected mutagenesis","volume":"16","author":"Smits BM","year":"2006","journal-title":"Pharmacogenet Genomics"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.14.2745"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211326200"},{"key":"e_1_2_8_25_2","first-page":"78","article-title":"A simple technique for rapid implantation of a permanent cannula into the rat brain ventricular system","volume":"29","author":"Brakkee JH","year":"1979","journal-title":"Lab Anim Sci"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(75)90103-4"},{"key":"e_1_2_8_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/385165a0"},{"key":"e_1_2_8_28_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.2.177"},{"key":"e_1_2_8_29_2","doi-asserted-by":"crossref","first-page":"4428","DOI":"10.1210\/endo.139.10.6332","article-title":"A C\u2010terminal fragment of Agouti\u2010related protein increases feeding and antagonizes the effect of \u03b1\u2010melanocyte stimulating hormone in vivo","volume":"139","author":"Rossi M.","year":"1998","journal-title":"Endocrinology"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(99)00465-3"},{"key":"e_1_2_8_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.2001.280.3.R814"},{"key":"e_1_2_8_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9384(99)00104-3"},{"key":"e_1_2_8_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2007.12.018"},{"key":"e_1_2_8_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/88423"},{"key":"e_1_2_8_35_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.4.5728"},{"key":"e_1_2_8_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.220409497"},{"key":"e_1_2_8_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.2000.279.1.R47"},{"key":"e_1_2_8_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/79254"},{"key":"e_1_2_8_39_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00562.2009"},{"key":"e_1_2_8_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.10.101"},{"key":"e_1_2_8_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.12.025"}],"container-title":["Obesity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Foby.2011.81","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Foby.2011.81","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/oby.2011.81","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T16:58:07Z","timestamp":1697561887000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1038\/oby.2011.81"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,3]]}},"alternative-id":["10.1038\/oby.2011.81"],"URL":"https:\/\/doi.org\/10.1038\/oby.2011.81","archive":["Portico"],"relation":{},"ISSN":["1930-7381","1930-739X"],"issn-type":[{"value":"1930-7381","type":"print"},{"value":"1930-739X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3]]},"assertion":[{"value":"2012-09-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}