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Although recent studies have depicted altered lipid metabolism as an underlying feature, the detailed mechanisms are still unclear. Here we describe a possible role in high\u2010fat diet (HFD)\u2010induced obesity for monoacylglycerol lipase (MGL), an enzyme that is also known to hydrolyze the endocannabinoid 2\u2010arachidonoylglycerol in brain. MGL\u2010deficient [MGL\u2010knockout (KO)] mice fed a HFD gained less body weight than wild\u2010type mice and were protected from insulin resistance and hepatic steatosis. Food intake and energy expenditure were not altered in MGL\u2010KO mice, but blood triglyceride levels after oral olive oil gavage were suppressed, indicating a role for MGL in intestinal fat absorption. Experiments with cannabinoid receptor type 1 (CB\n                    <jats:sub>1<\/jats:sub>\n                    )\/MGL double\u2010KO mice revealed that these phenotypes may include mechanisms that are independent of CB\n                    <jats:sub>1<\/jats:sub>\n                    \u2010receptor\u2013mediated endocannabinoid functions. We also noted that MGL\u2010KO mice had less preference for HFD over normal chow diet. Oral but not intraperitoneal lipid administration strongly suppressed the appetites of MGL\u2010KO and CB\n                    <jats:sub>1<\/jats:sub>\n                    \/MGL double\u2010KO mice, but not of wild\u2010type and CB\n                    <jats:sub>1<\/jats:sub>\n                    \u2010KO mice. Appetite suppression was reversed by vagotomy, suggesting involvement of MGL in the gut\u2013brain axis regulation of appetite. Our results provide mechanistic insights of MGL's role in diet\u2010induced obesity, lipid metabolic disorder, and regulation of appetite.\u2014Yoshida, K., Kita, Y., Tokuoka, S. M., Hamano, F., Yamazaki, M., Sakimura, K., Kano, M., Shimizu, T. Monoacylglycerol lipase deficiency affects diet\u2010induced obesity, fat absorption, and feeding behavior in CB1 cannabinoid receptor\u2013deficient mice. FASEB J. 33, 2484\u20132497 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201801203r","type":"journal-article","created":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T15:28:45Z","timestamp":1538148525000},"page":"2484-2497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Monoacylglycerol lipase deficiency affects diet\u2010induced obesity, fat absorption, and feeding behavior in CB\n                    <sub>1<\/sub>\n                    cannabinoid receptor\u2013deficient mice"],"prefix":"10.1096","volume":"33","author":[{"given":"Kenji","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Lipidomics The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kita","sequence":"additional","affiliation":[{"name":"Department of Lipidomics The University of Tokyo Tokyo Japan"},{"name":"Life Sciences Core Facility The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzumi M.","family":"Tokuoka","sequence":"additional","affiliation":[{"name":"Department of Lipidomics The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumie","family":"Hamano","sequence":"additional","affiliation":[{"name":"Department of Lipidomics The University of Tokyo Tokyo Japan"},{"name":"Life Sciences Core Facility The University of Tokyo Tokyo Japan"},{"name":"Department of Lipid Signaling National Center for Global Health and Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Cellular Neurobiology Brain Research Institute Niigata University Niigata Japan"},{"name":"Department of Neurology University of California, San Francisco San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Sakimura","sequence":"additional","affiliation":[{"name":"Department of Cellular Neurobiology Brain Research Institute Niigata University Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanobu","family":"Kano","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology Graduate School of Medicine The University of Tokyo Tokyo Japan"},{"name":"International Research Center for Neurointelligence (WPI-IRCN) University of Tokyo Institutes for Advanced Study (UTIAS) The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Lipidomics The University of Tokyo Tokyo Japan"},{"name":"Department of Lipid Signaling National Center for Global Health and Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2616"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.068304"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-13-0277"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.215434"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M058586"},{"key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"33122","DOI":"10.18632\/oncotarget.16529","article-title":"Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE2\/2 mice","volume":"8","author":"Vujic N.","year":"2017","journal-title":"Oncotarget"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.01.021"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043962"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5665-10.2011"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.10.5780"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0133663"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1152\/ajplegacy.1960.199.2.238","article-title":"Measurement of total energy and material balance in rats by means of doubly labeled water","volume":"199","author":"Lee J. 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