HYPOTHALAMIC NEURAL STEM CELL-DERIVED EXOSOMES RESTORE METABOLIC HOMEOSTASIS THROUGH BRAIN-FAT-AXIS

Hypothalamic neural stem cells (NSCs) are recognized as critical regulators of systemic metabolic homeostasis. However, the precise mechanisms by which endogenous NSCs regulate energy balance remain incompletely understood. Emerging evidence suggests that NSCs exert their regulatory functions through the secretion of paracrine signaling molecules, particularly exosomes. While NSC-derived exosomes have been implicated in aging-related phenotypes, their functional contribution to obesity and the underlying mechanisms remain unknown.
Here, using a high-fat diet (HFD)–induced obesity model, we demonstrate that endogenous hypothalamic NSC–derived exosomes are indispensable for body weight regulation. Selective ablation of hypothalamic Bmi1+ NSCs using a Bmi1-Cre–dependent iDTR system aggravated obesity, a phenotype robustly rescued by exosome administration. Conversely, genetic suppression of hypothalamic exosome secretion via a Bmi1-Cre–dependent AAV-DIO-shRab27a approach resulted in significant body weight gain, establishing a causal role for NSC-derived exosomes in metabolic control.
Mechanistically, the anti-obesity effects of NSC-derived exosomes required intact autonomic innervation to epididymal white adipose tissue (eWAT). Exosome treatment failed to reduce body weight following eWAT denervation, indicating that NSC-derived exosomes act through a brain–fat axis rather than direct peripheral mechanisms. Importantly, exosomes derived from human NSCs demonstrated comparable anti-obesity efficacy in mice. We identified three conserved microRNAs from human NSC-derived exosomes. AAV-mediated expression of their mouse orthologs as precursor miRNAs was sufficient to reproduce the metabolic effects of exosome treatment.
Together, these findings identify endogenous hypothalamic NSC-derived exosomes as novel, critical paracrine mediators of neural control over adipose tissue and energy balance, highlighting their translational potential for metabolic disorders.