{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:31:18Z","timestamp":1790721078686,"version":"4.1.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["FO2019-0122"],"award-info":[{"award-number":["FO2019-0122"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["FO2022-0717"],"award-info":[{"award-number":["FO2022-0717"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022-00242"],"award-info":[{"award-number":["2022-00242"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022-01643"],"award-info":[{"award-number":["2022-01643"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["award: 538-2013-8864"],"award-info":[{"award-number":["award: 538-2013-8864"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health & Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["R01MH136156"],"award-info":[{"award-number":["R01MH136156"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health & Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["R56MH129437; R01MH120170; R01MH124871; R01MH119084; R01MH118278; R01 MH124871"],"award-info":[{"award-number":["R56MH129437; R01MH120170; R01MH124871; R01MH119084; R01MH118278; R01 MH124871"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Independent Research Fund Denmark"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Growth and differentiation factor 15 (GDF15) is a significant player in cellular stress and energy homeostasis. GDF15 is elevated in cancer cachexia, chemotherapy-induced anorexia, hyperemesis gravidarum, and mitochondrial disorders. Here we analyze GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by low weight and persistent restriction of food intake. While no significant difference in plasma GDF15 concentration was seen across the three included groups; active AN, recovered AN, and healthy controls, a subgroup of study participants with high GDF15 plasma was noted to a significantly higher extent in the AN groups. Sparse partial least squares discriminant analysis (sPLS-DA) identified six markers related to inflammatory processes or cellular stress from a set of 74 markers that distinguished AN with high GDF15 from the rest, with fibroblast growth factor 21 (FGF21) being the most important contributor. Moreover, FGF21 plasma concentration was significantly higher in the group with high GDF15, suggesting an involvement of mitochondrial dysfunction. In fact, mitochondrial polygenic risk score (PRS) was significantly associated with AN risk in a large AN case-control cohort. In line with this, we also report elevated liver expression of GDF15 in the <jats:italic>anx\/anx<\/jats:italic> mouse displaying anorexia associated with mitochondrial dysfunction. We conclude that mitochondrial dysfunction should be further explored in AN. Clinical trials of GDF15 immunoneutralization in patients with AN and high levels of GDF15 are worthy of consideration.<\/jats:p>","DOI":"10.1038\/s41398-025-03425-0","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T06:49:20Z","timestamp":1750834160000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Elevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patients"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4019-7181","authenticated-orcid":false,"given":"Jingjing","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-9428","authenticated-orcid":false,"given":"Ruyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Millischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Stiernborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7657-8011","authenticated-orcid":false,"given":"Claire E.","family":"Tume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mehdinia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5619-8755","authenticated-orcid":false,"given":"Vanessa F.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4987-2718","authenticated-orcid":false,"given":"Catharina","family":"Lavebratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-6451","authenticated-orcid":false,"given":"Mikael","family":"Land\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7772-3264","authenticated-orcid":false,"given":"Cynthia M.","family":"Bulik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7676-4299","authenticated-orcid":false,"given":"Ida AK","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"3425_CR1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.cmet.2019.12.004","volume":"31","author":"T Borner","year":"2020","unstructured":"Borner T, Shaulson ED, Ghidewon MY, Barnett AB, Horn CC, Doyle RP, et al. GDF15 induces anorexia through nausea and emesis. Cell Metab. 2020;31:351\u201362.e355.","journal-title":"Cell Metab"},{"key":"3425_CR2","doi-asserted-by":"publisher","first-page":"123","DOI":"10.12688\/wellcomeopenres.14818.1","volume":"3","author":"CJ Petry","year":"2018","unstructured":"Petry CJ, Ong KK, Burling KA, Barker P, Goodburn SF, Perry JRB, et al. Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: a nested case-control study. Wellcome Open Res. 2018;3:123.","journal-title":"Wellcome Open Res"},{"key":"3425_CR3","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.cmet.2018.07.018","volume":"28","author":"VWW Tsai","year":"2018","unstructured":"Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1\/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 2018;28:353\u201368.","journal-title":"Cell Metab"},{"key":"3425_CR4","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.cmet.2020.10.023","volume":"32","author":"DM Breen","year":"2020","unstructured":"Breen DM, Kim H, Bennett D, Calle RA, Collins S, Esquejo RM, et al. GDF-15 neutralization alleviates platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and nonhuman primates. Cell Metab. 2020;32:938\u201350.e936.","journal-title":"Cell Metab"},{"key":"3425_CR5","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1743-7075-7-34","volume":"7","author":"I Dostalova","year":"2010","unstructured":"Dostalova I, Kavalkova P, Papezova H, Domluvilova D, Zikan V, Haluzik M. Association of macrophage inhibitory cytokine-1 with nutritional status, body composition and bone mineral density in patients with anorexia nervosa: the influence of partial realimentation. Nutr Metab. 2010;7:34.","journal-title":"Nutr Metab"},{"key":"3425_CR6","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1111\/j.1365-2265.2011.04139.x","volume":"76","author":"M Karczewska-Kupczewska","year":"2012","unstructured":"Karczewska-Kupczewska M, Kowalska I, Nikolajuk A, Adamska A, Otziomek E, Gorska M, et al. Hyperinsulinemia acutely increases serum macrophage inhibitory cytokine-1 concentration in anorexia nervosa and obesity. Clin Endocrinol. 2012;76:46\u201350.","journal-title":"Clin Endocrinol"},{"key":"3425_CR7","doi-asserted-by":"publisher","first-page":"bnaa007","DOI":"10.1210\/endrev\/bnaa007","volume":"41","author":"SM Lockhart","year":"2020","unstructured":"Lockhart SM, Saudek V, O\u2019Rahilly S. GDF15: a hormone conveying somatic distress to the brain. Endocr Rev. 2020;41:bnaa007.","journal-title":"Endocr Rev"},{"key":"3425_CR8","doi-asserted-by":"publisher","first-page":"eaan8732","DOI":"10.1126\/scitranslmed.aan8732","volume":"9","author":"Y Xiong","year":"2017","unstructured":"Xiong Y, Walker K, Min X, Hale C, Tran T, Komorowski R, et al. Long-acting MIC-1\/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci Transl Med. 2017;9:eaan8732.","journal-title":"Sci Transl Med"},{"key":"3425_CR9","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1530\/EJE-12-0466","volume":"167","author":"T Kempf","year":"2012","unstructured":"Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol. 2012;167:671\u20138.","journal-title":"Eur J Endocrinol"},{"key":"3425_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101589","volume":"65","author":"S Patel","year":"2022","unstructured":"Patel S, Haider A, Alvarez-Guaita A, Bidault G, El-Sayed Moustafa JS, Guiu-Jurado E, et al. Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice. Mol Metab. 2022;65:101589.","journal-title":"Mol Metab"},{"key":"3425_CR11","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1038\/s42255-024-01135-3","volume":"6","author":"AM Gurtan","year":"2024","unstructured":"Gurtan AM, Khalid S, Koch C, Khan MZ, Lamarche LB, Splawski I, et al. Identification and characterization of human GDF15 knockouts. Nat Metab. 2024;6:1913\u201321.","journal-title":"Nat Metab"},{"key":"3425_CR12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034868","volume":"7","author":"L Macia","year":"2012","unstructured":"Macia L, Tsai VW, Nguyen AD, Johnen H, Kuffner T, Shi YC, et al. Macrophage inhibitory cytokine 1 (MIC-1\/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PLoS ONE. 2012;7:e34868.","journal-title":"PLoS ONE"},{"key":"3425_CR13","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1038\/nm.4392","volume":"23","author":"SE Mullican","year":"2017","unstructured":"Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23:1150\u20137.","journal-title":"Nat Med"},{"key":"3425_CR14","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nature24042","volume":"550","author":"JY Hsu","year":"2017","unstructured":"Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017;550:255\u20139.","journal-title":"Nature"},{"key":"3425_CR15","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1038\/nm.4393","volume":"23","author":"PJ Emmerson","year":"2017","unstructured":"Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT, Gonciarz MD, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23:1215\u20139.","journal-title":"Nat Med"},{"key":"3425_CR16","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1038\/s41591-020-0945-x","volume":"26","author":"R Suriben","year":"2020","unstructured":"Suriben R, Chen M, Higbee J, Oeffinger J, Ventura R, Li B, et al. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nat Med. 2020;26:1264\u201370.","journal-title":"Nat Med"},{"key":"3425_CR17","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.1056\/NEJMoa2409515","volume":"391","author":"JD Groarke","year":"2024","unstructured":"Groarke JD, Crawford J, Collins SM, Lubaczewski S, Roeland EJ, Naito T, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391:2291\u2013303.","journal-title":"N Engl J Med"},{"key":"3425_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111947","volume":"42","author":"JY Kim-Muller","year":"2023","unstructured":"Kim-Muller JY, Song L, LaCarubba Paulhus B, Pashos E, Li X, Rinaldi A, et al. GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia. Cell Rep. 2023;42:111947.","journal-title":"Cell Rep"},{"key":"3425_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21309-x","volume":"12","author":"AB Klein","year":"2021","unstructured":"Klein AB, Nicolaisen TS, Ortenblad N, Gejl KD, Jensen R, Fritzen AM, et al. Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nat Commun. 2021;12:1041.","journal-title":"Nat Commun"},{"key":"3425_CR20","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.molmet.2017.12.016","volume":"9","author":"M Kleinert","year":"2018","unstructured":"Kleinert M, Clemmensen C, Sjoberg KA, Carl CS, Jeppesen JF, Wojtaszewski JFP, et al. Exercise increases circulating GDF15 in humans. Mol Metab. 2018;9:187\u201391.","journal-title":"Mol Metab"},{"key":"3425_CR21","unstructured":"Association AP. Diagnostic and statistical manual of mental disorders (DSM-5). American Psychiatric Publishing, Washington, DC; 2013."},{"key":"3425_CR22","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1038\/s41588-019-0439-2","volume":"51","author":"HJ Watson","year":"2019","unstructured":"Watson HJ, Yilmaz Z, Thornton LM, Hubel C, Coleman JRI, Gaspar HA, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet. 2019;51:1207\u201314.","journal-title":"Nat Genet"},{"key":"3425_CR23","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/nrn3745","volume":"15","author":"GJ Morton","year":"2014","unstructured":"Morton GJ, Meek TH, Schwartz MW. Neurobiology of food intake in health and disease. Nat Rev Neurosci. 2014;15:367\u201378.","journal-title":"Nat Rev Neurosci"},{"key":"3425_CR24","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1093\/oxfordjournals.jhered.a109987","volume":"75","author":"LJ Maltais","year":"1984","unstructured":"Maltais LJ, Lane PW, Beamer WG. Anorexia, a recessive mutation causing starvation in preweanling mice. J Hered. 1984;75:468\u201372.","journal-title":"J Hered"},{"key":"3425_CR25","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3389\/fnins.2019.00059","volume":"13","author":"IAK Nilsson","year":"2019","unstructured":"Nilsson IAK. The anx\/anx mouse - a valuable resource in anorexia nervosa research. Front Neurosci. 2019;13:59.","journal-title":"Front Neurosci"},{"key":"3425_CR26","doi-asserted-by":"publisher","first-page":"18108","DOI":"10.1073\/pnas.1114863108","volume":"108","author":"C Lindfors","year":"2011","unstructured":"Lindfors C, Nilsson IA, Garcia-Roves PM, Zuberi AR, Karimi M, Donahue LR, et al. Hypothalamic mitochondrial dysfunction associated with anorexia in the anx\/anx mouse. Proc Natl Acad Sci USA. 2011;108:18108\u201313.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3425_CR27","doi-asserted-by":"publisher","first-page":"e106463","DOI":"10.1371\/journal.pone.0106463","volume":"9","author":"VM Victor","year":"2014","unstructured":"Victor VM, Rovira-Llopis S, Saiz-Alarcon V, Sanguesa MC, Rojo-Bofill L, Banuls C, et al. Altered mitochondrial function and oxidative stress in leukocytes of anorexia nervosa patients. PLoS ONE. 2014;9:e106463.","journal-title":"PLoS ONE"},{"key":"3425_CR28","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.cmet.2019.08.019","volume":"30","author":"S Forsstrom","year":"2019","unstructured":"Forsstrom S, Jackson CB, Carroll CJ, Kuronen M, Pirinen E, Pradhan S, et al. Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metab. 2019;30:1040\u201354.e1047.","journal-title":"Cell Metab"},{"key":"3425_CR29","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1212\/WNL.0000000000003374","volume":"87","author":"JM Lehtonen","year":"2016","unstructured":"Lehtonen JM, Forsstrom S, Bottani E, Viscomi C, Baris OR, Isoniemi H, et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology. 2016;87:2290\u20139.","journal-title":"Neurology"},{"key":"3425_CR30","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/S1474-4422(11)70155-7","volume":"10","author":"A Suomalainen","year":"2011","unstructured":"Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 2011;10:806\u201318.","journal-title":"Lancet Neurol"},{"key":"3425_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.851534","volume":"10","author":"Y Li","year":"2022","unstructured":"Li Y, Li S, Qiu Y, Zhou M, Chen M, Hu Y, et al. Circulating FGF21 and GDF15 as biomarkers for screening, diagnosis, and severity assessment of primary mitochondrial disorders in children. Front Pediatr. 2022;10:851534.","journal-title":"Front Pediatr"},{"key":"3425_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/(SICI)1098-108X(200001)27:1<1::AID-EAT1>3.0.CO;2-Q","volume":"27","author":"CM Bulik","year":"2000","unstructured":"Bulik CM, Sullivan PF, Wade TD, Kendler KS. Twin studies of eating disorders: a review. Int J Eat Disord. 2000;27:1\u201320.","journal-title":"Int J Eat Disord"},{"key":"3425_CR33","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1176\/appi.ajp.157.3.469","volume":"157","author":"TD Wade","year":"2000","unstructured":"Wade TD, Bulik CM, Neale M, Kendler KS. Anorexia nervosa and major depression: shared genetic and environmental risk factors. Am J Psychiatry. 2000;157:469\u201371.","journal-title":"Am J Psychiatry"},{"key":"3425_CR34","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1001\/archpsyc.63.3.305","volume":"63","author":"CM Bulik","year":"2006","unstructured":"Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL. Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry. 2006;63:305\u201312.","journal-title":"Arch Gen Psychiatry"},{"key":"3425_CR35","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.cct.2018.09.015","volume":"74","author":"LM Thornton","year":"2018","unstructured":"Thornton LM, Munn-Chernoff MA, Baker JH, Jureus A, Parker R, Henders AK, et al. The anorexia nervosa genetics initiative (ANGI): overview and methods. Contemp Clin Trials. 2018;74:61\u201369.","journal-title":"Contemp Clin Trials"},{"key":"3425_CR36","unstructured":"Association AP. Diagnostic and statistical manual of mental disorders. 4th ed. American Psychiatric Publishing, Washington, DC; 1994."},{"key":"3425_CR37","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1093\/jalm\/jfac055","volume":"7","author":"Y Karusheva","year":"2022","unstructured":"Karusheva Y, Ratcliff M, Morseburg A, Barker P, Melvin A, Sattar N, et al. The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels. J Appl Lab Med. 2022;7:1388\u20131400.","journal-title":"J Appl Lab Med"},{"key":"3425_CR38","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1016\/j.bbi.2020.05.024","volume":"88","author":"IAK Nilsson","year":"2020","unstructured":"Nilsson IAK, Millischer V, Goteson A, Hubel C, Thornton LM, Bulik CM, et al. Aberrant inflammatory profile in acute but not recovered anorexia nervosa. Brain Behav Immun. 2020;88:718\u201324.","journal-title":"Brain Behav Immun"},{"key":"3425_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5","volume":"10","author":"T Ge","year":"2019","unstructured":"Ge T, Chen CY, Ni Y, Feng YA, Smoller JW. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat Commun. 2019;10:1776.","journal-title":"Nat Commun"},{"key":"3425_CR40","doi-asserted-by":"publisher","first-page":"D1541","DOI":"10.1093\/nar\/gkaa1011","volume":"49","author":"S Rath","year":"2021","unstructured":"Rath S, Sharma R, Gupta R, Ast T, Chan C, Durham TJ, et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021;49:D1541\u2013D1547.","journal-title":"Nucleic Acids Res"},{"key":"3425_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-023-02672-3","volume":"13","author":"R Zhang","year":"2023","unstructured":"Zhang R, Kuja-Halkola R, Borg S, Leppa V, Thornton LM, Birgegard A, et al. The impact of genetic risk for schizophrenia on eating disorder clinical presentations. Transl Psychiatry. 2023;13:366.","journal-title":"Transl Psychiatry"},{"key":"3425_CR42","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559\u201375.","journal-title":"Am J Hum Genet"},{"key":"3425_CR43","unstructured":"R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https:\/\/www.R-project.org\/. 2021."},{"key":"3425_CR44","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: elegant graphics for data analysis","author":"H Wickham","year":"2016","unstructured":"Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer-Verlag; 2016."},{"key":"3425_CR45","doi-asserted-by":"publisher","first-page":"e1005752","DOI":"10.1371\/journal.pcbi.1005752","volume":"13","author":"F Rohart","year":"2017","unstructured":"Rohart F, Gautier B, Singh A, Le Cao KA. mixOmics: an R package for \u2018omics feature selection and multiple data integration. PLoS Comput Biol. 2017;13:e1005752.","journal-title":"PLoS Comput Biol"},{"key":"3425_CR46","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41586-021-04133-7","volume":"600","author":"L Mulderrig","year":"2021","unstructured":"Mulderrig L, Garaycoechea JI, Tuong ZK, Millington CL, Dingler FA, Ferdinand JR, et al. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response. Nature. 2021;600:158\u201363.","journal-title":"Nature"},{"key":"3425_CR47","doi-asserted-by":"publisher","first-page":"12553","DOI":"10.1073\/pnas.1006962107","volume":"107","author":"MD Chau","year":"2010","unstructured":"Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA. 2010;107:12553\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3425_CR48","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.cmet.2013.04.005","volume":"17","author":"Z Lin","year":"2013","unstructured":"Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17:779\u201389.","journal-title":"Cell Metab"},{"key":"3425_CR49","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1016\/j.peptides.2007.10.007","volume":"28","author":"H Hsuchou","year":"2007","unstructured":"Hsuchou H, Pan W, Kastin AJ. The fasting polypeptide FGF21 can enter brain from blood. Peptides. 2007;28:2382\u20136.","journal-title":"Peptides"},{"key":"3425_CR50","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/s42255-022-00602-z","volume":"4","author":"V Pena-Leon","year":"2022","unstructured":"Pena-Leon V, Folgueira C, Barja-Fernandez S, Perez-Lois R, Da Silva Lima N, Martin M, et al. Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21. Nat Metab. 2022;4:901\u201317.","journal-title":"Nat Metab"},{"key":"3425_CR51","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cmet.2020.06.008","volume":"32","author":"SO Jensen-Cody","year":"2020","unstructured":"Jensen-Cody SO, Flippo KH, Claflin KE, Yavuz Y, Sapouckey SA, Walters GC, et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab. 2020;32:273\u201386.e276.","journal-title":"Cell Metab"},{"key":"3425_CR52","doi-asserted-by":"publisher","first-page":"6018","DOI":"10.1210\/en.2008-0816","volume":"149","author":"T Coskun","year":"2008","unstructured":"Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149:6018\u201327.","journal-title":"Endocrinology"},{"key":"3425_CR53","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1210\/jc.2009-1730","volume":"95","author":"PK Fazeli","year":"2010","unstructured":"Fazeli PK, Misra M, Goldstein M, Miller KK, Klibanski A. Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. J Clin Endocrinol Metab. 2010;95:369\u201374.","journal-title":"J Clin Endocrinol Metab"},{"key":"3425_CR54","doi-asserted-by":"publisher","first-page":"3627","DOI":"10.1210\/jc.2008-0746","volume":"93","author":"I Dostalova","year":"2008","unstructured":"Dostalova I, Kavalkova P, Haluzikova D, Lacinova Z, Mraz M, Papezova H, et al. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab. 2008;93:3627\u201332.","journal-title":"J Clin Endocrinol Metab"},{"key":"3425_CR55","doi-asserted-by":"publisher","first-page":"4601","DOI":"10.1172\/JCI83349","volume":"125","author":"PK Fazeli","year":"2015","unstructured":"Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y, et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest. 2015;125:4601\u201311.","journal-title":"J Clin Invest"},{"key":"3425_CR56","doi-asserted-by":"publisher","first-page":"3913","DOI":"10.1172\/JCI74915","volume":"124","author":"T Laeger","year":"2014","unstructured":"Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 2014;124:3913\u201322.","journal-title":"J Clin Invest"},{"key":"3425_CR57","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/sj.mp.4000418","volume":"3","author":"L Audi","year":"1998","unstructured":"Audi L, Mantzoros CS, Vidal-Puig A, Vargas D, Gussinye M, Carrascosa A. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry. 1998;3:544\u20137.","journal-title":"Mol Psychiatry"},{"key":"3425_CR58","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1006\/bmme.1996.2564","volume":"60","author":"FF Casanueva","year":"1997","unstructured":"Casanueva FF, Dieguez C, Popovic V, Peino R, Considine RV, Caro JF. Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery. Biochem Mol Med. 1997;60:116\u201320.","journal-title":"Biochem Mol Med"},{"key":"3425_CR59","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/sj.mp.4000282","volume":"2","author":"J Hebebrand","year":"1997","unstructured":"Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, et al. Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. Mol Psychiatry. 1997;2:330\u20134.","journal-title":"Mol Psychiatry"},{"key":"3425_CR60","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/S0006-3223(98)00292-3","volume":"46","author":"KA Gendall","year":"1999","unstructured":"Gendall KA, Kaye WH, Altemus M, McConaha CW, La Via MC. Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients. Biol Psychiatry. 1999;46:292\u20139.","journal-title":"Biol Psychiatry"},{"key":"3425_CR61","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.biopsych.2005.11.001","volume":"60","author":"K Holtkamp","year":"2006","unstructured":"Holtkamp K, Herpertz-Dahlmann B, Hebebrand K, Mika C, Kratzsch J, Hebebrand J. Physical activity and restlessness correlate with leptin levels in patients with adolescent anorexia nervosa. Biol Psychiatry. 2006;60:311\u20133.","journal-title":"Biol Psychiatry"},{"key":"3425_CR62","first-page":"40","volume":"9","author":"A Steensberg","year":"2003","unstructured":"Steensberg A. The role of IL-6 in exercise-induced immune changes and metabolism. Exerc Immunol Rev. 2003;9:40\u201347.","journal-title":"Exerc Immunol Rev"},{"key":"3425_CR63","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cmet.2018.12.016","volume":"29","author":"S Patel","year":"2019","unstructured":"Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 2019;29:707\u201318.e708.","journal-title":"Cell Metab"},{"key":"3425_CR64","doi-asserted-by":"publisher","first-page":"e0133362","DOI":"10.1371\/journal.pone.0133362","volume":"10","author":"VW Tsai","year":"2015","unstructured":"Tsai VW, Macia L, Feinle-Bisset C, Manandhar R, Astrup A, Raben A, et al. Serum levels of human MIC-1\/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLoS ONE. 2015;10:e0133362.","journal-title":"PLoS ONE"},{"key":"3425_CR65","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1210\/clinem\/dgab621","volume":"107","author":"A Imbert","year":"2022","unstructured":"Imbert A, Vialaneix N, Marquis J, Vion J, Charpagne A, Metairon S, et al. Network analyses reveal negative link between changes in adipose tissue GDF15 and BMI during dietary-induced weight loss. J Clin Endocrinol Metab. 2022;107:e130\u201342.","journal-title":"J Clin Endocrinol Metab"},{"key":"3425_CR66","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1038\/s41430-020-0568-9","volume":"74","author":"G Thom","year":"2020","unstructured":"Thom G, Dombrowski SU, Brosnahan N, Algindan YY, Rosario Lopez-Gonzalez M, Roditi G, et al. The role of appetite-related hormones, adaptive thermogenesis, perceived hunger and stress in long-term weight-loss maintenance: a mixed-methods study. Eur J Clin Nutr. 2020;74:622\u201332.","journal-title":"Eur J Clin Nutr"},{"key":"3425_CR67","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.018217","volume":"9","author":"H Wada","year":"2020","unstructured":"Wada H, Suzuki M, Matsuda M, Ajiro Y, Shinozaki T, Sakagami S, et al. Impact of smoking status on growth differentiation factor 15 and mortality in patients with suspected or known coronary artery disease: The ANOX study. J Am Heart Assoc. 2020;9:e018217.","journal-title":"J Am Heart Assoc"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03425-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03425-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03425-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T08:02:07Z","timestamp":1750838527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03425-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3425"],"URL":"https:\/\/doi.org\/10.1038\/s41398-025-03425-0","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]},"assertion":[{"value":"28 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"CMB is an author and royalty recipient from Pearson Education Inc. (unrelated to the content of the paper).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"215"}}