Exploring the contribution of hypothalamic gliosis to the metabolic and reproductive complications of hypogonadism: Translational implications for obesity-induced male hypogonadism.

Informations projet

GLIA-ReprObesity

N° de convention de subvention: 101109307

DOI

10.3030/101109307

Date de signature de la CE 2 Mai 2023

Date de début 1 Janvier 2024

Date de fin 31 Decembre 2026

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 285 140,64

Coordonné par

UNIVERSIDAD DE CORDOBA
Spain

Periodic Reporting for period 1 - GLIA-ReprObesity (Exploring the contribution of hypothalamic gliosis to the metabolic and reproductive complications of hypogonadism: Translational implications for obesity-induced male hypogonadism.)

Période du rapport: 2024-01-01 au 2025-12-31

Résumé du contexte et des objectifs généraux du projet

Obesity has become a global epidemic and remains one of the most urgent public health challenges worldwide. Its rise has been accompanied by a marked increase in obesity related comorbidities, including type 2 diabetes, hypertension, and cardiovascular disease. Beyond these well established metabolic consequences, a growing body of evidence indicates that obesity also contributes to hypogonadism, defined in males as abnormally low endogenous testosterone levels, a reproductive disorder that further elevates metabolic risk and worsens long term health outcomes.
Despite the clinical relevance of this association, the biological mechanisms linking metabolic dysfunction and reproductive impairment remain poorly understood. Recent clinical and preclinical studies associate high fat-diet consumption with hypothalamic gliosis, an inflammatory response involving microglia and astrocytes. However, whether gliosis is a driver, a consequence, or a co amplifier of hypogonadism remains unknown.
This project addresses this critical knowledge gap by using microglia-, the brain’s resident immune cells, and astrocyte-specific mouse models with increased or reduced inflammatory signaling. Thus, the project will unveil the potential role of hypothalamic gliosis as a central node linking metabolic dysregulation and reproductive dysfunction.
The expected impacts of this work are quite high and relevant. At the scientific level, the project will clarify a fundamental biological question with implications for endocrinology, metabolism, and neuroinflammation. At the translational level, identifying glial cells as potential upstream regulators of hypogonadism could reveal new therapeutic targets capable of mitigating both metabolic deterioration and reproductive impairment in patients with obesity.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The project has progressed substantially through a series of in vivo studies using glial specific genetically modified mouse models (ERα MGKO, IKKβ MGKO, and IKKβ AsKO) to investigate how microglial and astrocytic inflammatory pathways contribute to metabolic dysfunction and obesity associated reproductive dysfunction. The researcher performed comprehensive metabolic phenotyping including indirect calorimetry, body composition analysis, and glucose/insulin tolerance tests, and generated high quality datasets clarifying the metabolic consequences of glial specific signaling. Likewise, reproductive phenotyping following microglial and astrocytic manipulation has been completed, including assessments of estrous cyclicity, ovarian histology, luteinizing hormone (LH) and sex steroid levels, and reproductive gene expression. In parallel, the researcher acquired advanced expertise in confocal microscopy and quantitative image analysis (ImageJ, IMARIS), enabling detailed assessment of glial morphology, activation states, and interactions with key neuronal populations such as GnRH, Kiss1, and Tac2 neurons.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Through the project’s scientific achievements, we uncovered several key findings, including: 1) a protective role for microglial estrogen signaling in metabolic homeostasis; 2) the discovery that microglial proinflammatory NF‑κB signaling is essential for maintaining HPG axis integrity during obesity, preserving microglia-GnRH communication, and mitigating the HFD‑induced decline in ovulatory capacity; and 3) the identification of astrocytic inflammatory NF‑κB signaling as a major contributor to reproductive dysfunction in obesity. Together, these results refine our current understanding of how glial populations differentially contribute to metabolic and reproductive regulation. The work has produced robust preliminary data supporting multiple manuscripts and future competitive grant applications.