Epidemiological associations between metabolic dysfunction-associated fatty liver disease (MAFLD) and sleep disturbances point to shared mechanisms, yet the underlying central pathways remain unexplored. We hypothesized that high-fat diet (HFD)-induced MAFLD disrupts sleep architecture via hippocampal neuroinflammation and dysregulation of the IRS-1/Akt/mTOR signaling axis. Male BALB/c mice were fed a control diet (CD) or a 60% HFD for 16 weeks to induce MAFLD. Sleep-wake architecture was assessed by 24-h EEG/EMG recordings. We evaluated hepatic steatosis, serum cytokines, hippocampal histology, and hippocampal pro-inflammatory cytokines. Hippocampal expression and phosphorylation of IRS-1 (Ser307), Akt (Ser473), and mTOR (Ser2448) were analyzed by Western blot. HFD-fed mice developed hepatic steatosis, elevated liver enzymes, and increased serum tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). These mice exhibited reduced non‑rapid eye movement (NREM) and rapid eye movement (REM) sleep duration, severe sleep fragmentation (reflected by increased bout numbers and shorter mean bout durations), and diminished NREM sleep delta power. Cosinor analysis revealed a dampened circadian rhythm of NREM sleep delta power. In the hippocampus, HFD induced neuronal injury, elevated TNF-α and IL-1β levels, accompanied by a bifurcated signaling profile: increased p-IRS-1 (Ser307), decreased p-Akt (Ser473), and elevated p-mTOR (Ser2448). Our findings identify a putative liver-hippocampus-sleep axis in which MAFLD-driven systemic inflammation and hippocampal IRS-1/Akt/mTOR dysregulation are associated with profound sleep disruption, providing a framework for future mechanistic validation. Targeting this axis may offer new therapeutic strategies for sleep disorders in MAFLD.
