Cortical‐Hypothalamic Assembloids Uncover the Cortical Regulation of Hypothalamic Responses to Fatty Acid

Fatty acid (FA) overload imposes substantial stress on hypothalamic neurons, whilst whether cortical input could improve metabolic resilience of hypothalamic neurons remains poorly understood. Here, we reconstructed human cortical-hypothalamic assembloids (CO-HTO assembloids) to investigate how cortical input modulates hypothalamic responses to FA. Our results revealed that FA could impair neuronal survival, α-MSH secretion, and electrophysiological activity in hypothalamic organoids (HTOs). Remarkably, fusion with cortical organoids (COs) could prevent FA-induced apoptosis and functional defects, preserve mitochondrial respiration, and reduce lipid accumulation in HTOs. Also, transcriptomic and functional analyses revealed that cortical input could activate PGC1α-dependent mitochondrial biogenesis. Furthermore, pharmacological PGC1α activation or glutamate treatment rescued the FA-induced defects in HTOs. Collectively, our findings uncovered a cortico-hypothalamic regulatory axis and found glutamate-driven PGC1α activation might maintain hypothalamic neuronal stability and improve resilience to metabolic stress. Our CO-HTO assembloids provided a promising platform to investigate complex inter-regional communications and related neurological and metabolic disorders.