Abstract

Chronic stress is epidemiologically linked to metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. In mice exposed to chronic restraint stress (CRS), we observed weight-independent hepatic steatosis with marked degeneration of sympathetic fibers. Stress elevated circulating norepinephrine levels but blunted hepatic β-adrenergic/cyclic adenosine monophosphate (cAMP) signaling accompanied by downregulation of β3-adrenergic receptor (β3-AR), indicating hepatic catecholamine resistance. Blocking hepatic sympathetic input prevented stress-aggravated steatosis and restored β-adrenergic signaling, whereas pharmacologic activation of β3-AR with mirabegron alleviated stress-induced lipid accumulation. Pseudorabies virus retrograde tracing and neuronal circuit interrogation further showed that projection from the medial central amygdaloid nucleus (CeM) to paraventricular hypothalamic corticotropin-releasing hormone (CRHPVH) neurons mediated stress induced hepatic steatosis. Together, these results reveal a CeM-CRHPVH-hepatic sympathetic axis that couples central stress signaling to peripheral β-adrenergic desensitization and lipid dysregulation, thereby suggesting a potential therapeutic strategy for stress-related MASLD.