{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:19:00Z","timestamp":1785464340391,"version":"3.56.0"},"reference-count":70,"publisher":"National Academy of Sciences","issue":"37","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24gm1710007"],"award-info":[{"award-number":["24gm1710007"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"MEXT","doi-asserted-by":"crossref","award":["JPMXP1323015483"],"award-info":[{"award-number":["JPMXP1323015483"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,16]]},"abstract":"<jats:p>\n                    Adrenal lipomas are benign tumors containing ectopic adipose tissue in the adrenal gland, an organ that normally lacks both adipocytes and their progenitors. The origin of this ectopic fat remains enigmatic, and the absence of a genetic animal model has hindered its investigation. Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P\n                    <jats:sub>3<\/jats:sub>\n                    ], a key signaling lipid that regulates cellular growth and differentiation, is tightly regulated by the lipid phosphatases PTEN (phosphatase and tensin homolog) and SHIP2 (SH2-containing inositol phosphatase 2). Here, we demonstrate that simultaneous loss of\n                    <jats:italic toggle=\"yes\">Pten<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Ship2<\/jats:italic>\n                    in the adrenal cortex induces adrenal lipoma formation in mice. These lipomatous cells display both adipocyte-like morphology and adipocyte-specific gene expression. Lineage tracing revealed that these lipomas originate from the adrenal cortex. Mechanistically, PI(3,4,5)P\n                    <jats:sub>3<\/jats:sub>\n                    hyperaccumulation in the adrenal cortex activates AKT (AKT8 virus oncogene cellular homolog), leading to ectopic PPAR\u03b3 (peroxisome proliferator activated receptor gamma) expression, a key driver of adipocyte differentiation. This study suggests that the PI(3,4,5)P\n                    <jats:sub>3<\/jats:sub>\n                    \/AKT-driven transdifferentiation of adrenocortical cells may represent a central mechanism underlying adrenal lipoma formation, thereby providing insights into lipoma pathogenesis and cellular reprogramming in vivo.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2510306122","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:36:41Z","timestamp":1757432201000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Adrenal lipoma formation via PI(3,4,5)P\n                    <sub>3<\/sub>\n                    \/AKT-dependent transdifferentiation of adrenocortical cells into adipocytes"],"prefix":"10.1073","volume":"122","author":[{"given":"Shogo","family":"Yanai","sequence":"first","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5493-8112","authenticated-orcid":false,"given":"Hyeon-Cheol","family":"Lee-Okada","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Juntendo University Graduate School of Medicine","place":["Hongo, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9006-4831","authenticated-orcid":false,"given":"Fumiya","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University","place":["Maidashi, Higashi-ku, Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-0937","authenticated-orcid":false,"given":"Shin","family":"Morioka","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyoshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Yuguchi","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miko","family":"Oikawa","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6376-7629","authenticated-orcid":false,"given":"Hiroaki","family":"Kajiho","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-9877","authenticated-orcid":false,"given":"Takashi","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University","place":["Maidashi, Higashi-ku, Fukuoka, Japan"]},{"name":"Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University","place":["Maidashi, Higashi-ku, Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9219-8661","authenticated-orcid":false,"given":"Chikako","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioengineering, Graduate School of Engineering, Osaka Metropolitan University","place":["Sumiyoshi-ku, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-Ichirou","family":"Morohashi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kurume University School of Medicine","place":["Asahimachi, Kurume, Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5950-8808","authenticated-orcid":false,"given":"Akira","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine","place":["Chuo-ku, Kobe, Hyogo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-1553","authenticated-orcid":false,"given":"Takehiko","family":"Yokomizo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Juntendo University Graduate School of Medicine","place":["Hongo, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-3748","authenticated-orcid":false,"given":"Takehiko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo","place":["Yushima, Bunkyo-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.24"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00335-z"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08894"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.05.022"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00491-4"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2015.02.001"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00027"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000980"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add0422"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq029"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-18-0632"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.11.026"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00900-08"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa126"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1100"},{"key":"e_1_3_4_16_2","first-page":"159","article-title":"X-zone degeneration in the adrenal glands of adult and immature female mice","volume":"108","author":"Holmes P. V.","year":"1971","unstructured":"P. V. Holmes, A. D. Dickson, X-zone degeneration in the adrenal glands of adult and immature female mice. J. Anat. 108, 159\u2013168 (1971).","journal-title":"J. Anat."},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-16-0564"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(21)00178-9"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.4103\/0970-1591.152807"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-017-1473-4"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2013.03.021"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3290"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2009.06.001"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00035.2008"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.12.021"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1177\/1066896915595465"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20231"},{"key":"e_1_3_4_28_2","first-page":"1249","article-title":"Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I","volume":"6","author":"Lala D. S.","year":"1992","unstructured":"D. S. Lala, D. A. Rice, K. L. Parker, Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol. Endocrinol. 6, 1249\u20131258 (1992).","journal-title":"Mol. Endocrinol."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0128352"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.169136"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)37129-7"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113715"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90211-9"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03941-5"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-1-4"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2015.11.024"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080747"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311000200"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20513"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI151895"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf8271"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.06.018"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1013"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90006-X"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu10020130"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.07.038"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20150191"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2016.12.006"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705285104"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2021.104364"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.08.003"},{"key":"e_1_3_4_52_2","volume-title":"StatPearls","author":"Charifa A.","year":"2025","unstructured":"A. Charifa, C. E. Azmat, T. Badri, \u201cLipoma pathology\u201d in StatPearls (StatPearls Publishing, 2025)."},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.021"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10239"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.103.4.931"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.166801"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.2508\/chikusan.1.55"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1000400204"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.44.285"},{"key":"e_1_3_4_60_2","first-page":"217","article-title":"The adrenal X-zone of mice: Genetic analysis of its development with recombinant-inbred strains","volume":"46","author":"Janat M. F.","year":"1987","unstructured":"M. F. Janat, J. G. Shire, The adrenal X-zone of mice: Genetic analysis of its development with recombinant-inbred strains. Exp. Biol. 46, 217\u2013221 (1987).","journal-title":"Exp. Biol."},{"key":"e_1_3_4_61_2","first-page":"883","article-title":"A comparison of the X-zone of the adrenal cortex in two inbred strains of mice","volume":"1","author":"Daughaday W.","year":"1941","unstructured":"W. Daughaday, A comparison of the X-zone of the adrenal cortex in two inbred strains of mice. Cancer Res. 1, 883\u2013885 (1941).","journal-title":"Cancer Res."},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.55.343"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2023.05.003"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98394"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100462200"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00134-0"},{"key":"e_1_3_4_67_2","unstructured":"S. Yanai RNA-seq data from \u201cAdrenal lipoma formation via PI(3 4 5)PI\/AKT-dependent transdifferentiation of adrenocortical cells into adipocytes.\u201d DNA Data Bank of Japan. https:\/\/ddbj.nig.ac.jp\/search\/entry\/bioproject\/PRJDB19929. Deposited 7 January 2025."},{"key":"e_1_3_4_68_2","unstructured":"S. Kawamura RNA-seq data from \u201cInhibiting SCAP\/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis.\u201d Sequence Read Archive repository. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA715216. Deposited 17 March 2021."},{"key":"e_1_3_4_69_2","unstructured":"B. S. Gosis RNA-seq data from \u201cInhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.\u201d Sequence Read Archive repository. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA672904. Deposited 28 October 2020."},{"key":"e_1_3_4_70_2","unstructured":"L. Wang RNA-seq data from \u201cSelective activation of Gs signaling in adipocytes causes striking metabolic improvements in mice.\u201d Sequence Read Archive repository. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA545137. Deposited 28 May 2019."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2510306122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:36:51Z","timestamp":1757432211000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2510306122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":70,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2025,9,16]]}},"alternative-id":["10.1073\/pnas.2510306122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2510306122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,9]]},"assertion":[{"value":"2025-04-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2510306122"}}