title: Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1.
abstract: Throughout evolution, organisms have devised strategies to limit fertility in case of prolonged starvation. In mammals, the liver plays a central role in the orchestration of mechanisms allowing for the maintenance of energy homeostasis. We here demonstrate that dietary amino acids regulate the transcriptional activity of hepatic estrogen receptor alpha (ERα) through an mTOR-dependent mechanism. As a result of ERα activation, hepatic IGF-1 mRNA and blood IGF-1 are increased. Conversely, calorie restriction or selective ablation of ERα in the liver decrease blood IGF-1 to levels inadequate for the correct proliferation of the lumen epithelium in the uterus and the progression of the estrous cycle. We propose that the liver acts as critical mediator of energetic and reproductive functions responsible for the blockade of the estrous cycle in case of protein scarcity. Our findings may provide novel insights to understand the cause of selected forms of infertility and metabolic alterations in women after menopause.
authors.affiliation: Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, 20133, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Della Torre
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Rando
authors.forename: Clara
authors.initials: C
authors.lastname: Meda
authors.forename: Alessia
authors.initials: A
authors.lastname: Stell
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Cristian
authors.initials: C
authors.lastname: Ibarra
authors.forename: Paolo
authors.initials: P
authors.lastname: Magni
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012098:Reproduction / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000596:Amino Acids; D047628:Estrogen Receptor alpha; D007334:Insulin-Like Growth Factor I; D058570:TOR Serine-Threonine Kinases