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Here, we reconstructed human cortical\u2010hypothalamic assembloids (CO\u2010HTO assembloids) to investigate how cortical input modulates hypothalamic responses to FA. Our results revealed that FA could impair neuronal survival, \u03b1\u2010MSH secretion, and electrophysiological activity in hypothalamic organoids (HTOs). Remarkably, fusion with cortical organoids (COs) could prevent FA\u2010induced apoptosis and functional defects, preserve mitochondrial respiration, and reduce lipid accumulation in HTOs. Also, transcriptomic and functional analyses revealed that cortical input could activate PGC1\u03b1\u2010dependent mitochondrial biogenesis. Furthermore, pharmacological PGC1\u03b1 activation or glutamate treatment rescued the FA\u2010induced defects in HTOs. Collectively, our findings uncovered a cortico\u2010hypothalamic regulatory axis and found glutamate\u2010driven PGC1\u03b1 activation might maintain hypothalamic neuronal stability and improve resilience to metabolic stress. Our CO\u2010HTO assembloids provided a promising platform to investigate complex inter\u2010regional communications and related neurological and metabolic disorders.<\/jats:p>","DOI":"10.1111\/cpr.70207","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T23:51:02Z","timestamp":1775519462000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cortical\u2010Hypothalamic Assembloids Uncover the Cortical Regulation of Hypothalamic Responses to Fatty Acid"],"prefix":"10.1111","volume":"59","author":[{"given":"Mengdan","family":"Tao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Department of Neurology, Affiliated Zhongda Hospital Southeast University  Nanjing China"},{"name":"Institute of Stem Cell and Neural Regeneration School of Pharmacy, Nanjing Medical University  Nanjing 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