{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:49:54Z","timestamp":1780512594643,"version":"3.54.1"},"reference-count":148,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adipocytes produce the hormone leptin, a hormone that links energy availability to reproductive function by permitting activation of the hypothalamic\u2013pituitary\u2013gonadal (HPG) axis. Loss-of-function mutations in the long leptin receptor isoform (LEPRb) disrupt intracellular signaling pathways, including the Janus kinase 2 (JAK2)\/signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, resulting in central leptin resistance and impaired neuroendocrine control of reproduction. Evidence from human monogenic obesity syndromes, animal models, and neuroendocrine studies indicates that LEPRb mutations disrupt hypothalamic circuitry upstream of gonadotropin-releasing hormone (GnRH) neurons, impairing GnRH pulsatility and leading to hypogonadotropic hypogonadism (HH) and infertility. This review synthesizes molecular, translational, and clinical data highlighting the central role of kisspeptin-mediated signaling in leptin-dependent reproductive regulation. Current therapeutic limitations are discussed alongside emerging approaches, including kisspeptin-based therapies and receptor-targeted strategies. Elucidating how LEPRb dysfunction disrupts metabolic\u2013reproductive integration may provide insights into both rare monogenic conditions and common obesity-associated reproductive dysfunction.<\/jats:p>","DOI":"10.3390\/ijms27052482","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:16:12Z","timestamp":1773051372000},"page":"2482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Leptin Receptor b (LEPRb) Mutations Disrupt Hypothalamic Control of the Reproductive Axis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9553-6803","authenticated-orcid":false,"given":"Athanasios","family":"Zikopoulos","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine and Surgery, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3333-2620","authenticated-orcid":false,"given":"Efthalia","family":"Moustakli","sequence":"additional","affiliation":[{"name":"Department of Nursing, School of Health Sciences, University of Ioannina, 4th Kilometer National Highway Str. Ioannina-Athens, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8892-2768","authenticated-orcid":false,"given":"Periklis","family":"Katopodis","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilis Sebastian","family":"Paraschos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Corewell Health Hospital, 4700 Schaefer Road Suite 310, Dearborn, MI 48126, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-1521","authenticated-orcid":false,"given":"Anastasios","family":"Potiris","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismini","family":"Anagnostaki","sequence":"additional","affiliation":[{"name":"Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini Lydia","family":"Vogiatzoglou","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3076-818X","authenticated-orcid":false,"given":"Konstantinos","family":"Zacharis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, General Hospital of Lamia, 35100 Lamia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-9190","authenticated-orcid":false,"given":"Theodoros","family":"Karampitsakos","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-4182","authenticated-orcid":false,"given":"Konstantinos","family":"Zikopoulos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofoklis","family":"Stavros","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fontana, R., and Torre, S. 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