Leptin Receptor b (LEPRb) Mutations Disrupt Hypothalamic Control of the Reproductive Axis.
Document Type
Article
Publication Date
3-8-2026
Publication Title
International journal of molecular sciences
Abstract
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.
Volume
27
First Page
2482
Recommended Citation
Zikopoulos A, Moustakli E, Katopodis P, Paraschos VS, Potiris A, Anagnostaki I et al Leptin receptor b (leprb) mutations disrupt hypothalamic control of the reproductive axis. Int J Mol Sci. 2026 Mar 8;27(5):2482. doi: 10.3390/ijms27052482. PMID: 41828698
DOI
10.3390/ijms27052482vvvv
ISSN
1422-0067
PubMed ID
41828698