Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits
Abstract
Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD determined a low-grade inflammation in the hypothalamus, significantly inducing microglial activation, expression and immunopositivity of IL-6, as well as GLUT4 and reduced immunopositivity for KISS1 receptor, whose mRNA expression was negatively correlated to glucose intolerance. Correcting glucose metabolism with obetcholic acid improved hypothalamic alterations, reducing GLUT4 and IL-6 immunopositivity and significantly increasing GnRH mRNA, without, however, preventing HFD-related HH. No significant effects at the hypothalamic level were observed after systemic anti-inflammatory treatment (infliximab). Our results suggest that HFD-induced metabolic derangements negatively affect GnRH neuron function through an inflammatory injury at the hypothalamic level.
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The distinction between a functional and an organic form of hypogonadism is captious because even diet-induced hypogonadotropic hypogonadism is associated with distinct organic alterations within the hypothalamus, the testis and the penis.
“The distinction between a functional and an organic form of HG is, in some ways, captious because, as demonstrated in our preclinical model, even diet-induced hypogonadotropic HG is associated with distinct, organic alterations within the hypothalamus, the testis and the penis [606162].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [61]
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- Authors
- Morelli, A., Sarchielli, E., Comeglio, P., Filippi, S., Vignozzi, L., Marini, M., Rastrelli, G., Maneschi, E., Cellai, I., Persani, L., Adorini, L., Vannelli, G. B., & Maggi, M.
- Affiliations
- University of Florence (IT)
- University of Milan (IT)
- Intercept Pharmaceuticals (United States) (US)
- Istituto Nazionale Biostrutture e Biosistemi (IT)
- Corresponding author
- Maggi, Mario
- ORCID
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 382
- Issue
- 1
- Pages
- 107-119
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2074119828
- Cited by
- 107
- References
- 56
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 6 · 2019: 10 · 2018: 8 · 2017: 10 · 2016: 5 · 2015: 8 · 2014: 10 · 2013: 1
- FWCI
- 9.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Funders
- Italian Minister of Health
- FIRB (2010RBFR10VJ56 002)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- metabolic syndrome, high-fat diet, hypogonadotropic hypogonadism, GnRH neurons, hypothalamus, preoptic area, hypothalamic inflammation, microglial activation, interleukin-6, glucose transporter 4, KISS1 receptor, impaired glucose tolerance, obeticholic acid, infliximab, anti-inflammatory therapy
- MeSH terms
- Infliximab, Animals, Antibodies, Monoclonal, Chenodeoxycholic Acid, Gene Expression Regulation, Immunohistochemistry, Inflammation, Gonadotropin-Releasing Hormone, Male, Neurons, Preoptic Area, Rabbits, RNA, Messenger, Biomarkers, Metabolic Syndrome, Receptors, G-Protein-Coupled, Glucose Transporter Type 4, Diet, High-Fat
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