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Single-nucleus transcriptomic sequencing (snRNA-seq) was performed on pooled hypothalami from each group: aged male Norway brown rats treated with 17\u03b1-estradiol (O.T), aged controls (O), and young controls (Y). Supervised clustering of neurons (based on neuropeptides\/receptors) evaluated subtype responses to aging and 17\u03b1-estradiol. Aging-induced elevation of neuronal cellular metabolism, stress, and reduced synapse formation-related pathways were significantly attenuated by 17\u03b1-estradiol. Neuron population analysis showed that subtypes regulating food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17\u03b1-estradiol. 17\u03b1-estradiol increased serum oxytocin (Oxt) and hypothalamic-pituitary-gonadal (HPG) axis activity (elevated plasma Gnrh, total testosterone; reduced estradiol). Gnrh1 upregulation mediated its effects on energy homeostasis, neural synapse, and stress response. Notably,\n                    <jats:italic>Crh<\/jats:italic>\n                    neurons in O.T showed prominent stress phenotypes, distinct from\n                    <jats:italic>Agrp\/Ghrl<\/jats:italic>\n                    neurons. Thus, HPG axis and energy metabolism may be key 17\u03b1-estradiol targets in male hypothalamus. Additionally, our results demonstrate that supervised clustering (based on neuropeptides\/receptors) effectively assesses the responses of hypothalamic neuron subtypes to aging and 17\u03b1-estradiol treatment.\n                  <\/jats:p>","DOI":"10.7554\/elife.100346","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T10:27:08Z","timestamp":1725964028000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.100346","source":"Crossref","is-referenced-by-count":0,"title":["The effects of 17\u03b1-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus"],"prefix":"10.7554","volume":"13","author":[{"given":"Lei","family":"Li","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Peking Union Medical College 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