Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits.
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.
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Annamaria
A
Morelli
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Erica
E
Sarchielli
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Paolo
P
Comeglio
Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Experimental and Clinical Biomedical Sciences and Department of NEUROFARBA, University of Florence, 50139 Florence, Italy.
Sandra
S
Filippi
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Linda
L
Vignozzi
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Mirca
M
Marini
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Giulia
G
Rastrelli
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Elena
E
Maneschi
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Ilaria
I
Cellai
Department of Clinical Sciences and Community Health, University of Milan, Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, 20149-Milan, Italy; CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari della Malattie della Riproduzione), 20122 Milan, Italy.
Luca
L
Persani
Intercept Pharmaceuticals, New York, NY, United States.
Luciano
L
Adorini
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Gabriella B
GB
Vannelli
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy; CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari della Malattie della Riproduzione), 20122 Milan, Italy; I.N.B.B. - Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy. Electronic address: mario.maggi@unifi.it.
Mario
M
Maggi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood / Q000209:etiology*; D000069285:Infliximab; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D051275:Glucose Transporter Type 4; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid; D007987:Gonadotropin-Releasing Hormone; D000069285:Infliximab
GLUT4; Glucose intolerance; Hypogonadotropic hypogonadism; Hypothalamic inflammation; IL-6; Metabolic syndrome