[en] Estrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes-specialized glia lining the floor and walls of the third ventricle-integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons.
METHODS: Using mouse models, including mice floxed for Esr1 (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with virogenic, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females.
RESULTS: In ovariectomized mice, chemogenetic activation of tanycytes significantly reduced LH pulsatile release, mimicking the effects of direct NPY neuron activation. In intact mice, tanycytes were crucial for the estrogen-mediated control of GnRH/LH release, with tanycytic ERα activation suppressing fasting-induced NPY neuron activation. Selective knockout of Esr1 in tanycytes altered estrous cyclicity and fertility in female mice and affected estrogen's ability to inhibit refeeding in fasting mice. The absence of ERα signaling in tanycytes increased Npy transcripts and body weight in intact mice and prevented the estrogen-mediated decrease in food intake as well as increase in energy expenditure and fatty acid oxidation in ovariectomized mice.
CONCLUSIONS: Our findings underscore the pivotal role of tanycytes in the neuroendocrine coupling of reproduction and metabolism, with potential implications for its age-related deregulation after menopause.
SIGNIFICANCE STATEMENT: Our investigation reveals that tanycytes, specialized glial cells in the brain, are key interpreters of estrogen signals for orexigenic NPY neurons in the hypothalamus. Disrupting tanycytic estrogen receptors not only alters fertility in female mice but also impairs the ability of estrogens to suppress appetite. This work thus sheds light on the critical role played by tanycytes in bridging the hormonal regulation of cyclic reproductive function and appetite/feeding behavior. This understanding may have potential implications for age-related metabolic deregulation after menopause.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Fernandois, Daniela; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Rusidze, Marian; Institute of Metabolic and Cardiovascular Diseases (I2MC) Equipe 4, Inserm U1297UPS, CHU, Toulouse, France
Mueller-Fielitz, Helge; Institute of Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
Sauve, Florent; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Deligia, Eleonora; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Silva, Mauro S B; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Evrard, Florence ; Université de Liège - ULiège > GIGA ; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Franco-García, Aurelio; Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, Spain, Instituto Murciano de Investigación Biosanitaria (IMIB), Pascual Parrilla, Murcia, Spain
Mazur, Daniele; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Martinez-Corral, Ines; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Jouy, Nathalie; PLBS UAR 2014 - US41, France
Rasika, S; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Maurage, Claude-Alain; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Giacobini, Paolo; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Nogueiras, Ruben; CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
Dehouck, Benedicte; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France
Schwaninger, Markus; Institute of Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
Lenfant, Francoise; Institute of Metabolic and Cardiovascular Diseases (I2MC) Equipe 4, Inserm U1297UPS, CHU, Toulouse, France
Prevot, Vincent; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, F-59000 Lille, France. Electronic address: vincent.prevot@inserm.fr
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