Leptin Receptor b (LEPRb) Mutations Disrupt Hypothalamic Control of the Reproductive Axis

TL;DR

LEPRb mutations disrupt the brain's control of reproduction by impairing leptin signaling, leading to infertility and potential insights into obesity-related reproductive issues.

Contribution

This review highlights the role of LEPRb mutations in reproductive dysfunction and explores emerging therapies like kisspeptin-based treatments.

Findings

LEPRb mutations impair JAK2/STAT3, PI3K, and MAPK pathways, causing central leptin resistance.

Disrupted hypothalamic circuitry upstream of GnRH neurons leads to hypogonadotropic hypogonadism.

Kisspeptin-mediated signaling plays a central role in leptin-dependent reproductive regulation.

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.

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