Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Cell Proliferation

DOI: 10.1111/cpr.70207