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Promoting thermogenesis and a functional increase in the browning of white adipocytes may counteract obesity. On the other hand, the molecular mechanism that regulates brown and beige fat\u2010mediated thermogenesis is unclear. This article reports a molecular network led by cytoplasmic FMR1\u2010interacting protein 2 (CYFIP2) that negatively regulates adipocyte browning in white adipocytes. Although the function of CYFIP2 in Fragile X Syndrome (FXS) and autism have been reported, its physiological roles in adipocytes remain elusive. Therefore, this study examined the physiological consequences of its deprivation in cultured 3T3\u2010L1 white adipocytes using loss\u2010of\u2010function studies. Combined real\u2010time quantitative reverse\u2010transcription polymerase chain reaction and immunoblot analysis showed that the loss of <jats:italic>CYFIP2<\/jats:italic> induces fat browning, as evidenced by the gene and protein expression levels of the brown fat\u2010associated markers. A deficiency of <jats:italic>CYFIP2<\/jats:italic> promoted mitochondrial biogenesis and significantly enhanced the expression of the core set beige fat\u2010specific genes (<jats:italic>Cd137<\/jats:italic>, <jats:italic>Cidea<\/jats:italic>, <jats:italic>Cited1<\/jats:italic>, <jats:italic>Tbx1<\/jats:italic>, and <jats:italic>Tmem26<\/jats:italic>) and proteins (PGC\u20101\u03b1, PRDM16, and UCP1). In addition, a <jats:italic>CYFIP2<\/jats:italic> deficiency promoted lipid catabolism and suppressed adipogenesis, lipogenesis, and autophagy. A mechanistic study showed that the loss of <jats:italic>CYFIP2<\/jats:italic> induces browning in white adipocytes, independently via the activation of mTORC1 and suppression of the GABA\u2010BR signaling pathway. The present data revealed a previously unidentified mechanism of CYFIP2 in the browning of white adipocytes and emphasized the potential of CYFIP2 as a pharmacotherapeutic target for treating obesity and other metabolic disorders.<\/jats:p>","DOI":"10.1002\/jcb.30231","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T06:08:49Z","timestamp":1646201329000},"page":"863-877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Loss of cytoplasmic FMR1\u2010interacting protein 2 (CYFIP2) induces browning in 3T3\u2010L1 adipocytes via repression of GABA\u2010BR and activation of mTORC1"],"prefix":"10.1002","volume":"123","author":[{"given":"Subramani","family":"Manigandan","sequence":"first","affiliation":[{"name":"Department of Biotechnology Daegu University  Gyeongsan Gyeongbuk Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-2282","authenticated-orcid":false,"given":"Jong Won","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Daegu University  Gyeongsan Gyeongbuk Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"1","article-title":"The genetics of obesity: from discovery to biology","volume":"23","author":"Loos","year":"2021","journal-title":"Nat Rev Genet"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.199"},{"key":"e_1_2_11_4_1","unstructured":"World Health Organization (WHO).Obesity and Overweight. 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