{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:44:30Z","timestamp":1785775470057,"version":"3.56.0"},"reference-count":44,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt","doi-asserted-by":"publisher","award":["01GM2203E"],"award-info":[{"award-number":["01GM2203E"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rhythm Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bardet\u2013Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective single-center observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine functions and suggest partially weight-independent therapeutic effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag293","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:41:42Z","timestamp":1784893302000},"source":"Crossref","is-referenced-by-count":0,"title":["Melanocortin-4 receptor regulation of endocrine axes and clinical effects of setmelanotide"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4389-0903","authenticated-orcid":false,"given":"Tom","family":"H\u00fchne","sequence":"first","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Steidel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Holland","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilja","family":"Finkelberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordula","family":"Kiewert","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3635-6418","authenticated-orcid":false,"given":"Lars","family":"Pape","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5617-4451","authenticated-orcid":false,"given":"Lars","family":"Dinkelbach","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0918-9204","authenticated-orcid":false,"given":"Metin","family":"Cetiner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics II, University Hospital Essen, University of Duisburg-Essen , Essen 45147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"issue":"1","key":"2026080311463151600_dgag293-B1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/ejhg.2012.115","article-title":"Bardet-Biedl syndrome","volume":"21","author":"Forsythe","year":"2013","journal-title":"Eur J Hum Genet"},{"key":"2026080311463151600_dgag293-B2","doi-asserted-by":"crossref","DOI":"10.1007\/s00112-024-02030-7","article-title":"Das Bardet-Biedl syndrome","author":"Cetiner","year":"2024","journal-title":"Monatsschr Kinderheilkd"},{"issue":"11","key":"2026080311463151600_dgag293-B3","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/s41431-024-01634-7","article-title":"Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations","volume":"32","author":"Dollfus","year":"2024","journal-title":"Eur J Hum Genet"},{"issue":"5","key":"2026080311463151600_dgag293-B4","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1210\/jc.2017-01459","article-title":"The endocrine and metabolic characteristics of a large Bardet-Biedl syndrome clinic population","volume":"103","author":"Mujahid","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026080311463151600_dgag293-B5","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1136\/jmg.36.6.437","article-title":"Original articles new criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey","volume":"36","author":"Beales","year":"1999","journal-title":"J Med Genet"},{"issue":"3","key":"2026080311463151600_dgag293-B6","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMra1514009","article-title":"Mechanisms, pathophysiology, and management of obesity","volume":"376","author":"Heymsfield","year":"2017","journal-title":"N Engl J Med"},{"issue":"6588","key":"2026080311463151600_dgag293-B7","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/382250a0","article-title":"Role of leptin in the neuroendocrine response to fasting","volume":"382","author":"Ahlma","year":"1996","journal-title":"Nature"},{"issue":"2","key":"2026080311463151600_dgag293-B8","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1172\/JCI111747","article-title":"Comparative study of pituitary-thyroid hormone economy in fasting and hypothyroid rats","volume":"75","author":"St Germain","year":"1985","journal-title":"J Clin Invest"},{"key":"2026080311463151600_dgag293-B9","doi-asserted-by":"crossref","DOI":"10.1016\/j.psyneuen.2023.106365","article-title":"Neuroendocrine adaptations to starvation","volume":"157","author":"Amorim","year":"2023","journal-title":"Psychoneuroendocrinology"},{"issue":"Suppl 2","key":"2026080311463151600_dgag293-B10","article-title":"Physiology of weight regain: lessons from the classic Minnesota Starvation Experiment on human body composition regulation","volume":"22","author":"Dulloo","year":"2021","journal-title":"Obes Rev"},{"issue":"24","key":"2026080311463151600_dgag293-B11","doi-asserted-by":"crossref","first-page":"7309","DOI":"10.1113\/JP272770","article-title":"Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone","volume":"594","author":"Tan","year":"2016","journal-title":"J Physiol"},{"issue":"6","key":"2026080311463151600_dgag293-B12","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.celrep.2018.04.018","article-title":"Diet-induced growth is regulated via acquired leptin resistance and engages a Pomc-somatostatin-growth hormone circuit","volume":"23","author":"L\u00f6hr","year":"2018","journal-title":"Cell Rep"},{"issue":"2","key":"2026080311463151600_dgag293-B13","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.peptides.2005.01.033","article-title":"Role of melanocortin signaling in the regulation of the hypothalamic\u2013pituitary\u2013thyroid (HPT) axis","volume":"27","author":"Lechan","year":"2006","journal-title":"Peptides (NY)"},{"issue":"2930","key":"2026080311463151600_dgag293-B14","doi-asserted-by":"crossref","first-page":"431","DOI":"10.4414\/smw.2007.11774","article-title":"Obesity is associated with increased serum TSH level, independent of thyroid function","volume":"137","author":"Bastemir","year":"2007","journal-title":"Swiss Med Wkly"},{"issue":"3","key":"2026080311463151600_dgag293-B15","doi-asserted-by":"crossref","first-page":"R53","DOI":"10.1530\/REP-13-0509","article-title":"Kisspeptin and energy balance in reproduction","volume":"147","author":"De Bond","year":"2014","journal-title":"Reproduction"},{"issue":"5","key":"2026080311463151600_dgag293-B16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s00018-012-1095-1","article-title":"Leptin signaling and circuits in puberty and fertility","volume":"70","author":"Elias","year":"2012","journal-title":"Cell Mol Life Sci"},{"key":"2026080311463151600_dgag293-B17","doi-asserted-by":"crossref","first-page":"RP100722","DOI":"10.7554\/eLife.100722.4","article-title":"POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons","volume":"13:","author":"Talbi","year":"2025","journal-title":"Elife"},{"issue":"1","key":"2026080311463151600_dgag293-B18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1477-7827-7-24","article-title":"Reduction in corpora lutea number in obese melanocortin-4-receptor-deficient mice","volume":"7","author":"Sandrock","year":"2009","journal-title":"Reprod Biol Endocrinol"},{"issue":"3","key":"2026080311463151600_dgag293-B19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1530\/REP-16-0341","article-title":"Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice","volume":"153","author":"Chen","year":"2017","journal-title":"Reproduction"},{"key":"2026080311463151600_dgag293-B20","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.metabol.2016.12.004","article-title":"Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction","volume":"70","author":"Xu","year":"2017","journal-title":"Metabolism"},{"issue":"3","key":"2026080311463151600_dgag293-B21","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1210\/clinem\/dgaf483","article-title":"Impact of the melanocortin-4 receptor agonist setmelanotide on MASLD and kidney function in Bardet-Biedl syndrome","volume":"111","author":"H\u00fchne","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026080311463151600_dgag293-B22","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1186\/s13023-025-03835-9","article-title":"Patient and caregiver experiences with a patient-support program for setmelanotide treatment of patients with Bardet-Biedl syndrome","volume":"20","author":"Finkelberg","year":"2025","journal-title":"Orphanet J Rare Dis"},{"key":"2026080311463151600_dgag293-B23","doi-asserted-by":"crossref","unstructured":"H\u00fchne T . 2026. Supplementary data related to the orignal article \u2018melanocortin-4 receptor regulation of endocrine axes and clinical effects of setmelanotide\u2019 by H\u00fchne et al. (2026). Figshare. DOI:10.6084\/m9.figshare.33028739.","DOI":"10.2139\/ssrn.6457902"},{"issue":"1","key":"2026080311463151600_dgag293-B24","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjaminit","year":"1995","journal-title":"J R Stat Soc Series B Stat Methodol"},{"issue":"1","key":"2026080311463151600_dgag293-B25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/cen.13973","article-title":"Reversible male hypogonadotropic hypogonadism due to energy deficit","volume":"91","author":"Wong","year":"2019","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"1","key":"2026080311463151600_dgag293-B26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3390\/nu13010113","article-title":"Eight days of water-only fasting promotes favorable changes in the functioning of the urogenital system of middle-aged healthy men","volume":"13","author":"Letkiewicz","year":"2020","journal-title":"Nutrients"},{"key":"2026080311463151600_dgag293-B27","first-page":"E1","article-title":"Control of fertility by metabolic cues","volume":"270","author":"Wade","year":"1996","journal-title":"Am J Physiol"},{"issue":"6","key":"2026080311463151600_dgag293-B28","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.3390\/ijms22062827","article-title":"Leptin modulates the response of brown adipose tissue to negative energy balance: implication of the GH\/IGF-I axis","volume":"22","author":"Barrios","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"2026080311463151600_dgag293-B29","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.arr.2008.01.002","article-title":"Caloric restriction: impact upon pituitary function and reproduction","volume":"7","author":"Martin","year":"2008","journal-title":"Ageing Res Rev"},{"issue":"1","key":"2026080311463151600_dgag293-B30","doi-asserted-by":"crossref","first-page":"391.e13","DOI":"10.1016\/j.fertnstert.2009.02.023","article-title":"Reversible hypogonadism in Bardet-Biedl syndrome","volume":"92","author":"Desai","year":"2009","journal-title":"Fertil Steril"},{"issue":"1","key":"2026080311463151600_dgag293-B31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3390\/ijms25010179","article-title":"The molecular basis of male infertility in obesity: a literature review","volume":"25","author":"George","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"3","key":"2026080311463151600_dgag293-B32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1530\/REP-10-0119","article-title":"Obesity and the pubertal transition in girls and boys","volume":"140","author":"Burt Solorzano","year":"2010","journal-title":"Reproduction"},{"issue":"6","key":"2026080311463151600_dgag293-B33","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.rbmo.2014.02.004","article-title":"Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility","volume":"28","author":"Wright","year":"2014","journal-title":"Reprod Biomed Online"},{"key":"2026080311463151600_dgag293-B34","first-page":"23","article-title":"The effect of simple obesity on growth and growth hormone","volume":"40","author":"Vanderschueren-Lodeweyckx","year":"1993","journal-title":"Horm Res"},{"issue":"2","key":"2026080311463151600_dgag293-B35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1046\/j.1467-789X.2002.00055.x","article-title":"A review of the literature of Bardet\u2013Biedl disease and report of three cases associated with metabolic syndrome and diagnosed after the age of fifty","volume":"3","author":"Iannello","year":"2002","journal-title":"Obes Rev"},{"issue":"6","key":"2026080311463151600_dgag293-B36","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cmet.2011.10.009","article-title":"NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways","volume":"14","author":"Vella","year":"2011","journal-title":"Cell Metab"},{"issue":"7","key":"2026080311463151600_dgag293-B37","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1089\/thy.2023.0173","article-title":"Regulation of thyroid hormone levels by hypothalamic thyrotropin-releasing hormone neurons","volume":"33","author":"Costa-E-Sousa","year":"2023","journal-title":"Thyroid"},{"key":"2026080311463151600_dgag293-B38","first-page":"607","article-title":"Metabolic and functional cross talk between the thyroid and liver","volume":"35","author":"Chng","year":"2025","journal-title":"Thyroid"},{"issue":"1","key":"2026080311463151600_dgag293-B39","doi-asserted-by":"crossref","first-page":"19790","DOI":"10.1038\/s41598-024-70242-8","article-title":"Efficacy and safety of Resmetirom, a selective thyroid hormone receptor-\u03b2 agonist, in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis","volume":"14","author":"Suvarna","year":"2024","journal-title":"Sci Rep"},{"issue":"12","key":"2026080311463151600_dgag293-B40","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/S2213-8587(22)00277-7","article-title":"Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstr\u00f6m syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period","volume":"10","author":"Haqq","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"2026080311463151600_dgag293-B41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4274\/jcrpe.galenos.2022.2022-5-21","article-title":"Specific functions of melanocortin 3 receptor (MC3R)","volume":"15","author":"Yanik","year":"2023","journal-title":"J Clin Res Pediatr Endocrinol"},{"issue":"2","key":"2026080311463151600_dgag293-B42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.peptides.2005.01.025","article-title":"The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)","volume":"27","author":"Marks","year":"2006","journal-title":"Peptides (NY)"},{"issue":"1","key":"2026080311463151600_dgag293-B43","doi-asserted-by":"crossref","first-page":"34938","DOI":"10.1038\/srep34938","article-title":"Effects of melanocortin 3 and 4 receptor deficiency on energy homeostasis in rats","volume":"6","author":"You","year":"2016","journal-title":"Sci Rep"},{"key":"2026080311463151600_dgag293-B44","author":"U.S. Food and Drug Administration, Center for Drug Evaluation and Research"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag293\/70422772\/dgag293.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag293\/70422772\/dgag293.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:46:44Z","timestamp":1785772004000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article\/doi\/10.1210\/clinem\/dgag293\/8748677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":44,"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgag293","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]},"article-number":"dgag293"}}