Temporal Adaptations of Liver Physiology and Molecular Mechanisms under Chronic Stress Conditions

Stress disrupts homeostasis in rodents via internal/external stressors, with chronic exposure causing metabolic and hepatic dysfunction. The liver is the primary organ of metabolism and it is particularly susceptible to long-term stress. The present study was performed to investigate the effect of different durations of restraint stress (RS) on the mechanisms controlling energy balance, inflammation, and apoptosis in the liver of male albino rats. Sixty rats (250 ± 10 g) were divided into control, handled, and RS groups (1, 2, 4, or 6 weeks of daily 3-hour sessions). Biochemical analysis showed significant increases in Insulin, TC, TAG, LDL-c and VLDL-c levels. At the same time, significant decreases were observed in glucagon, IGF-1 and HDL levels. Gene expression analysis in the liver showed significant upregulation of TNF-α, INFγ, IL-8, IL-1 β, mTOR, P53, TGF-β and down regulation of IL-10, AMPK, GLP-1R, ACC and NRF2. These findings demonstrate that prolonged RS disrupts metabolic homeostasis by promoting oxidative stress, inflammation, and apoptosis while suppressing antioxidant defences. In conclusion, our findings have significant translational implications, placing chronic restraint stress as a powerful causative of metabolic disease. The results demonstrate a multi-faceted pathological process where stress simultaneously stimulates a pro-inflammatory and pro-oxidative state while disrupting cellular metabolism. The suppression of the central energy sensor AMPK and GLP-1R, coupled with the activation of the anabolic mTOR pathway, explains the resulting systemic insulin resistance and dyslipidemia. This molecular signature is a feature of human metabolic disorders, suggesting that individuals exposed to chronic stress may be more susceptible to conditions like type 2 diabetes and atherosclerosis.