AdipoRon treatment modulates hypothalamic clock-gene expression, oxidative stress, and SIRT1/NRF2/HO-1-related signaling in male mice subjected to chronic sleep restriction.

Adequate sleep is essential for biological rhythmicity and metabolic homeostasis, but chronic sleep restriction (CSR), a common modern challenge, disrupts hypothalamic function and contributes to circadian dysregulation, oxidative stress, and metabolic disturbances. This study investigated the effects of AdipoRon (AR), an adiponectin receptor agonist, on CSR-associated changes in hypothalamic clock-gene expression, oxidative stress markers, and components of the SIRT1/NRF2/HO-1 signaling axis. Male mice were assigned to control, CSR, CSR + Melatonin (Mel), and CSR + AR groups. Animals underwent 21 days of sleep restriction (18 h/day) using the multiple-platform approach and received intranasal AR (10 µg) or Mel (40 µg) daily for 21 days. Circadian clock genes (Clock, Bmal1, Per1, and Cry1), oxidative stress markers (malondialdehyde, superoxide dismutase, glutathione peroxidase, and total antioxidant capacity), and components of the SIRT1/NRF2/HO-1 pathway were assessed in the hypothalamus. Serum lipid profile and liver enzymes were also measured. The results showed that CSR induced marked alterations in hypothalamic clock-related gene expression, accompanied by increased oxidative stress and reduced expression of SIRT1/NRF2/HO-1 pathway-related proteins. In addition, CSR reduced body weight gain and triglyceride levels while increasing low-density lipoprotein (LDL), aspartate transaminase (AST), and alanine aminotransferase (ALT). In contrast, AR treatment partially reversed CSR-associated alterations in clock-related gene expression, attenuated oxidative stress, reduced LDL and ALT levels, and increased the expression of SIRT1/NRF2/HO-1 pathway-related proteins. These findings suggest that AR may mitigate CSR-associated molecular and metabolic alterations and warrant further investigation into its underlying mechanisms.