Total cholesterol (TC) and the cholesterol oxidation product 27-hydroxycholesterol (27-OHC) are both increased in the elderly. Accumulating evidence has linked 27-OHC to glucose metabolism in the brain, while docosahexaenoic acid (DHA) has been shown to positively regulate the 27-OHC levels. However, it is unclear whether DHA may affect glucose metabolism in the brain by regulating 27-OHC levels. In this study, we hypothesized that DHA supplementation would modulate TC levels and reduce 27-OHC levels, thereby improving brain glucose metabolism in SAMP8 mice. The mice were assigned into the Control group and DHA dietary supplementation group. The study evaluated cholesterol levels, 27-OHC levels, and glucose metabolism in the brain. The results showed that DHA supplementation decreased serum levels of TC, low-density lipoprotein cholesterol (LDL-C), and increased levels of high-density lipoprotein cholesterol (HDL-C); and improved the glucose-corrected standardized uptake value of cortex, hippocampus, and whole brain regions in SAMP8 mice. In conclusion, supplementation of DHA could regulate the cholesterol composition and reduce the level of 27-OHC, thereby improving brain glucose metabolism in SAMP8 mice.

The global obesity epidemic has increased the burden of metabolic diseases. Dietary interventions are key to managing obesity and improving metabolic health. Intermittent fasting (IF) has emerged as a promising chrononutritional intervention that may modulate metabolic metabolic homeostasis through timed eating–fasting cycles. This review examines four main IF patterns:time-restricted feeding (TRF), alternate day fasting (ADF), the 5:2 fasting, and the 4:3 fasting, and evaluates their effects on body weight, glucose homeostasis, insulin sensitivity, and lipid profiles. Furthermore, it delineates the mechanistic pathways through which IF confers metabolic benefits beyond caloric restriction alone: (1) alleviating insulin resistance by enhancing the intestinal mucosal barrier and upregulating GLP-1 expression suppressing endotoxemia-related inflammation; (2) restoring circadian rhythmicity in the expression of metabolism-related genes to correct metabolic dysregulation; (3) increasing energy expenditure and lipid oxidation via short-chain fatty acid-mediated browning of white adipose tissue (WAT); and (4) enhancing cellular autophagy through activation of the SIRT3–AMPK–mTOR signaling pathway, thereby improving overall metabolic function. Evidence supports IF as a potentially effective alternative for obesity and metabolic disorders through chronobiological mechanisms. However, potential adverse effects like hypoglycemia and adherence challenges highlight the need for individualized approaches in clinical practice.