Academic Journal
Leptin Receptor b (LEPRb) Mutations Disrupt Hypothalamic Control of the Reproductive Axis.
| Τίτλος: | Leptin Receptor b (LEPRb) Mutations Disrupt Hypothalamic Control of the Reproductive Axis. |
|---|---|
| Συγγραφείς: | Zikopoulos A; Department of Reproductive Medicine and Surgery, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK., Moustakli E; Department of Nursing, School of Health Sciences, University of Ioannina, 4th Kilometer National Highway Str. Ioannina-Athens, 45500 Ioannina, Greece., Katopodis P; Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece., Paraschos VS; Department of Obstetrics and Gynecology, Corewell Health Hospital, 4700 Schaefer Road Suite 310, Dearborn, MI 48126, USA., Potiris A; Third Department of Obstetrics and Gynecology, University General Hospital 'ATTIKON', Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece., Anagnostaki I; Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece., Vogiatzoglou AL; Third Department of Obstetrics and Gynecology, University General Hospital 'ATTIKON', Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece., Zacharis K; Department of Obstetrics and Gynecology, General Hospital of Lamia, 35100 Lamia, Greece., Karampitsakos T; Third Department of Obstetrics and Gynecology, University General Hospital 'ATTIKON', Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece., Zikopoulos K; Department of Obstetrics & Gynecology, University Hospital of Ioannina, 45500 Ioannina, Greece., Stavros S; Third Department of Obstetrics and Gynecology, University General Hospital 'ATTIKON', Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece. |
| Πηγή: | International journal of molecular sciences [Int J Mol Sci] 2026 Mar 08; Vol. 27 (5). Date of Electronic Publication: 2026 Mar 08. |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| Ιατρικοί όροι (MeSH): | Receptors, Leptin*/genetics , Receptors, Leptin*/metabolism , Hypothalamus*/metabolism , Reproduction*/genetics , Mutation*, Leptin/metabolism ; Gonadotropin-Releasing Hormone/metabolism ; Kisspeptins/metabolism ; Hypogonadism/genetics ; Hypogonadism/metabolism ; Humans ; Animals ; Hypothalamic-Pituitary-Gonadal Axis ; Signal Transduction |
| Περίληψη: | Adipocytes produce the hormone leptin, a hormone that links energy availability to reproductive function by permitting activation of the hypothalamic-pituitary-gonadal (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-reproductive integration may provide insights into both rare monogenic conditions and common obesity-associated reproductive dysfunction. |
| References: | J Clin Med. 2025 May 08;14(10):. (PMID: 40429279) Endocrinology. 2011 Apr;152(4):1541-50. (PMID: 21325051) J Clin Med. 2025 Apr 10;14(8):. (PMID: 40283443) Front Endocrinol (Lausanne). 2019 May 22;10:329. (PMID: 31178828) Am J Hum Genet. 2024 Dec 5;111(12):2668-2674. (PMID: 39561769) Endocr Connect. 2023 Sep 27;12(11):. (PMID: 37615381) Physiol Rev. 2018 Oct 1;98(4):2381-2430. (PMID: 30156493) J Ovarian Res. 2023 Oct 25;16(1):208. (PMID: 37880734) Front Endocrinol (Lausanne). 2018 Jan 05;8:367. (PMID: 29354094) Curr Genomics. 2025;26(4):278-289. (PMID: 41235102) Ann Endocrinol (Paris). 2022 Jun;83(3):159-163. (PMID: 35436503) Nature. 2024 Dec;636(8041):198-205. (PMID: 39478220) Front Endocrinol (Lausanne). 2024 May 17;15:1369248. (PMID: 38828407) Diabetes. 2022 Apr 1;71(4):694-705. (PMID: 35061034) Int J Mol Sci. 2024 Nov 21;25(23):. (PMID: 39684197) Vet World. 2025 Jun;18(6):1614-1633. (PMID: 40689179) Int J Mol Sci. 2021 Apr 20;22(8):. (PMID: 33924072) Front Physiol. 2021 Feb 18;12:639417. (PMID: 33679451) Biomolecules. 2019 Feb 16;9(2):. (PMID: 30781447) Am J Physiol Regul Integr Comp Physiol. 2016 Jun 1;310(11):R1258-66. (PMID: 27101301) Clin Endocrinol (Oxf). 2021 Nov;95(5):702-715. (PMID: 34368982) Pediatr Endocrinol Diabetes Metab. 2023;29(2):118-123. (PMID: 37728464) Andrology. 2026 May;14(4):1002-1016. (PMID: 39834030) Spermatogenesis. 2015 Jan 26;4(2):e996025. (PMID: 26413400) Best Pract Res Clin Endocrinol Metab. 2025 Jul;39(4):102022. (PMID: 40634221) Dev Med Child Neurol. 2023 Jan;65(1):38-49. (PMID: 35851656) Biomolecules. 2025 Jun 28;15(7):. (PMID: 40723812) Life (Basel). 2021 Dec 22;12(1):. (PMID: 35054403) Hum Reprod Update. 2016 Apr;22(3):358-81. (PMID: 26715597) Annu Rev Physiol. 2017 Feb 10;79:209-236. (PMID: 28192062) Cells. 2021 Jan 11;10(1):. (PMID: 33440789) Endocr Rev. 2024 Jan 4;45(1):30-68. (PMID: 37467734) Nutrients. 2016 Feb 11;8(2):87. (PMID: 26875986) Andrology. 2026 May;14(4):1029-1063. (PMID: 39901824) Biophys J. 2025 Nov 18;124(22):4018-4033. (PMID: 40878132) Asian J Androl. 2016 May-Jun;18(3):373-80. (PMID: 26908067) Nat Commun. 2023 Mar 31;14(1):1797. (PMID: 37002197) Genes Dev. 2025 Jul 1;39(13-14):792-807. (PMID: 40393800) Mol Ther. 2025 Nov 5;33(11):5316-5326. (PMID: 41047628) Dis Model Mech. 2017 Jun 1;10(6):679-689. (PMID: 28592656) Int J Mol Sci. 2023 Jun 26;24(13):. (PMID: 37445852) Endocrinology. 2011 Jun;152(6):2302-10. (PMID: 21427219) Trends Endocrinol Metab. 2010 Jan;21(1):10-6. (PMID: 19854659) J Reprod Dev. 2018 Dec 14;64(6):469-476. (PMID: 30298825) Eur J Med Genet. 2018 Aug;61(8):465-467. (PMID: 29545012) Endocrinology. 2023 Jan 9;164(3):. (PMID: 36683455) Horm Mol Biol Clin Investig. 2021 Dec 20;43(2):235-247. (PMID: 34931507) Front Endocrinol (Lausanne). 2021 May 18;12:585887. (PMID: 34084149) Front Endocrinol (Lausanne). 2017 Feb 21;8:30. (PMID: 28270795) Front Neuroendocrinol. 2022 Apr;65:100977. (PMID: 34999056) Int J Mol Sci. 2024 May 26;25(11):. (PMID: 38891991) Life Sci. 2016 May 15;153:207-12. (PMID: 27212704) Medicina (Kaunas). 2024 Feb 05;60(2):. (PMID: 38399562) J Clin Invest. 2011 Jan;121(1):355-68. (PMID: 21183787) Neuron. 2004 Jun 24;42(6):983-91. (PMID: 15207242) Int J Mol Sci. 2021 Aug 26;22(17):. (PMID: 34502119) BMC Neurosci. 2010 Jul 13;11:81. (PMID: 20626877) Metabolism. 2023 Jul;144:155556. (PMID: 37121307) Reprod Biol Endocrinol. 2025 Jul 7;23(1):97. (PMID: 40624700) Diabetol Metab Syndr. 2024 Feb 1;16(1):33. (PMID: 38302999) Int J Mol Sci. 2020 Jun 23;21(12):. (PMID: 32586047) Mol Psychiatry. 1999 Jan;4(1):8-12, 6-7. (PMID: 10089000) Endocr Connect. 2025 Sep 29;14(9):. (PMID: 40932169) Horm Res Paediatr. 2025;98(3):327-335. (PMID: 38718777) Nutr Metab (Lond). 2021 Apr 13;18(1):39. (PMID: 33849593) J Clin Endocrinol Metab. 2024 Sep 16;109(10):2602-2616. (PMID: 38470203) Trends Immunol. 2020 Feb;41(2):113-125. (PMID: 31959515) Int J Mol Sci. 2023 Jan 11;24(2):. (PMID: 36674935) J Nutr. 1998 Dec;128(12):2299-306. (PMID: 9868173) Front Endocrinol (Lausanne). 2024 Sep 26;15:1464803. (PMID: 39391877) Metabolism. 2024 Dec;161:156053. (PMID: 39490439) Int J Mol Sci. 2023 Oct 13;24(20):. (PMID: 37894835) Curr Cardiol Rev. 2025;21(5):e1573403X356019. (PMID: 39931847) Cells. 2024 Nov 19;13(22):. (PMID: 39594663) Front Endocrinol (Lausanne). 2021 Aug 24;12:722441. (PMID: 34504472) Int J Mol Sci. 2022 Aug 25;23(17):. (PMID: 36077028) Obesity (Silver Spring). 2014 Feb;22 Suppl 1:S1-S17. (PMID: 24574081) Int J Mol Sci. 2021 Jun 16;22(12):. (PMID: 34208585) Asian J Androl. 2015 Mar-Apr;17(2):219-20. (PMID: 25412675) Sci Transl Med. 2023 Nov 22;15(723):eadd4897. (PMID: 37992152) Surg Obes Relat Dis. 2021 Aug;17(8):1449-1456. (PMID: 34083135) Chem Biol. 2012 Jan 27;19(1):51-9. (PMID: 22284354) Front Endocrinol (Lausanne). 2020 Jun 16;11:354. (PMID: 32655492) Reprod Biol Endocrinol. 2025 Sep 1;23(1):120. (PMID: 40890764) J Inflamm Res. 2022 Feb 25;15:1349-1364. (PMID: 35241923) Front Neurosci. 2023 Oct 31;17:1238528. (PMID: 38027481) J Clin Res Pediatr Endocrinol. 2024 Apr 29;16(4):379-400. (PMID: 38683021) J Clin Immunol. 2023 Aug;43(6):1326-1359. (PMID: 37140667) Horm Mol Biol Clin Investig. 2014 Mar;17(3):109-28. (PMID: 25372735) Elife. 2024 Jul 15;13:. (PMID: 39007235) Metab Brain Dis. 2024 Dec;39(8):1613-1636. (PMID: 39083184) J Clin Med. 2025 Nov 22;14(23):. (PMID: 41375608) Cell Rep Med. 2023 Sep 19;4(9):101187. (PMID: 37659411) Endocrinol Diabetes Metab Case Rep. 2022 Aug 1;2022:. (PMID: 36001025) J Turk Ger Gynecol Assoc. 2024 Dec 10;25(4):247-258. (PMID: 39658934) Front Cell Dev Biol. 2021 Jul 09;9:695623. (PMID: 34307371) Mol Cell Endocrinol. 2018 Mar 5;463:131-141. (PMID: 29102564) Ann N Y Acad Sci. 2024 Oct;1540(1):21-46. (PMID: 39287750) Front Endocrinol (Lausanne). 2018 Apr 26;9:188. (PMID: 29755406) Fertil Steril. 2012 May;97(5):1183-91. (PMID: 22341640) J Mol Graph Model. 2025 Mar;135:108912. (PMID: 39608136) Mol Metab. 2019 Jul;25:131-141. (PMID: 31076350) Reprod Sci. 2023 Mar;30(3):802-822. (PMID: 35799018) Nat Rev Neurosci. 2018 Feb;19(2):95-105. (PMID: 29321684) Med Rev (2021). 2022 Aug 9;2(4):363-384. (PMID: 37724323) Cell Mol Life Sci. 2013 Mar;70(5):841-62. (PMID: 22851226) Endocrinology. 2021 Feb 1;162(2):. (PMID: 33165520) Endocrinol Metab (Seoul). 2015 Jun;30(2):124-41. (PMID: 26194072) Eur J Endocrinol. 2022 Apr 21;186(6):G9-G49. (PMID: 35353710) Front Endocrinol (Lausanne). 2023 Nov 01;14:1266730. (PMID: 38027184) Sci Rep. 2023 Sep 20;13(1):15631. (PMID: 37730735) Endocr Rev. 2019 Apr 1;40(2):669-710. (PMID: 30698671) Diabetes Metab Syndr Obes. 2019 Jan 25;12:191-198. (PMID: 30774404) Front Endocrinol (Lausanne). 2024 Jun 24;15:1413068. (PMID: 38978625) Front Neuroendocrinol. 1999 Oct;20(4):317-63. (PMID: 10569281) Trends Mol Med. 2021 Aug;27(8):807-823. (PMID: 34210598) Metabolism. 2021 Mar;116:154438. (PMID: 33221380) Int J Mol Sci. 2023 Jun 06;24(12):. (PMID: 37372963) Transl Androl Urol. 2018 Jul;7(Suppl 3):S348-S352. (PMID: 30159241) Int J Mol Sci. 2023 Jan 31;24(3):. (PMID: 36769012) Mutagenesis. 2024 Apr 24;39(3):157-171. (PMID: 38332115) Genes (Basel). 2019 May 07;10(5):. (PMID: 31067764) Eur J Med Res. 2010 Nov 4;15 Suppl 2:50-4. (PMID: 21147620) Curr Opin Pharmacol. 2022 Dec;67:102321. (PMID: 36427399) Cell Mol Life Sci. 2016 Apr;73(7):1457-77. (PMID: 26786898) J Endocr Soc. 2018 Sep 17;3(1):27-41. (PMID: 30560226) J Lipid Res. 2021;62:100105. (PMID: 34390703) Endocrinol Metab Clin North Am. 2024 Jun;53(2):293-305. (PMID: 38677871) Endocrinology. 2009 Jun;150(6):2805-12. (PMID: 19179437) Adipocyte. 2025 Dec;14(1):2508188. (PMID: 40415699) Ann Pediatr Endocrinol Metab. 2022 Sep;27(3):176-182. (PMID: 36203268) Front Endocrinol (Lausanne). 2021 Sep 09;12:724632. (PMID: 34566891) Front Endocrinol (Lausanne). 2022 Nov 21;13:951938. (PMID: 36479214) Biomedicines. 2019 Jan 04;7(1):. (PMID: 30621143) Endocrinology. 2025 Mar 24;166(5):. (PMID: 40130278) Front Endocrinol (Lausanne). 2023 Jun 29;14:1184530. (PMID: 37455902) |
| Contributed Indexing: | Keywords: JAK2/STAT3 signaling; Kiss1; central leptin resistance; gonadotropin-releasing hormone; hypothalamic circuitry; infertility; metabolic–reproductive integration; neuroendocrine regulation; pubertal failure; receptor signaling defects |
| Substance Nomenclature: | 0 (Receptors, Leptin) 0 (Leptin) 33515-09-2 (Gonadotropin-Releasing Hormone) 0 (Kisspeptins) |
| Entry Date(s): | Date Created: 20260314 Date Completed: 20260711 Latest Revision: 20260813 |
| Update Code: | 20260813 |
| PubMed Central ID: | PMC12985556 |
| DOI: | 10.3390/ijms27052482 |
| PMID: | 41828698 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1422-0067 |
|---|---|
| DOI: | 10.3390/ijms27052482 |