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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,4,18]]},"abstract":"<jats:p>\n                    Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of\n                    <jats:italic>Tet3<\/jats:italic>\n                    , which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety\/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2300015120","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T15:09:44Z","timestamp":1681139384000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-8305","authenticated-orcid":false,"given":"Haining","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Department of Obstetrics and Gynecology and Center for Reproductive Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-7406","authenticated-orcid":false,"given":"Jonatas","family":"Catarino","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4895-1185","authenticated-orcid":false,"given":"Da","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Center of Reproductive Medicine, National Health Commission Key Laboratory of Reproductive and Genetic Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-2157","authenticated-orcid":false,"given":"Beibei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Center of Reproductive Medicine, National Health Commission Key Laboratory of Reproductive and Genetic Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Bing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas L.","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-8465","authenticated-orcid":false,"given":"Yingqun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520"},{"name":"Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2020.596381"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40337-021-00481-x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11920-022-01319-2"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0000000000000739"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16176"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3147"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.02.024"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13339-3"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-00300-8"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-01004-x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-019-0438-1"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.08.032"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4274"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108267"},{"key":"e_1_3_4_15_2","article-title":"Melanocortin 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