The reactive oxygen species (ROS) signaling in the hypothalamus is crucial for energy homeostasis; however, excessive ROS exacerbates oxidative stress and promotes hypothalamic dysfunctioning. Also, the emergence of insulin insensitivity and obesity are directly linked to hypothalamic disturbance. The objective of the present study was to determine the effectiveness of gallic acid (GA) as a therapeutic agent against long-term exposure to a high-fat diet (HFD) on the antioxidant profile in the hypothalamus in correlation with glucose tolerance, insulin resistance, and inflammatory parameters. For the current study total of 24 female Swiss-albino mice were divided into 4 groups, 6 animals each for the duration of 90 days. Group I control, group II HFD, group III HFD + GA (50 mg/kg b. wt orally), and group IV GA (50 mg/kg b. wt orally). At the end of the experiment, biochemical, antioxidative, inflammatory, and histological parameters were assessed. Although there was no change in daily food consumption, the administration of GA in HFD-treated mice resulted in a notable reduction in body weight (p ≤ 0.001) and improved hypothalamic superoxide dismutase (SOD) (p = 0.019), catalase (CAT) (p ≤ 0.001), and glutathione peroxidase (GPx) (p ≤ 0.001) in the HFD-treated group. The administration of GA has reduced (p ≤ 0.001) serum glucose, cholesterol, and triglyceride and increased (p ≤ 0.001) high-density lipoprotein (HDL) levels. Moreover, HFD group for 90 days exhibited a decreased tolerance to a 2-h intraperitoneal glucose tolerance test (GTT). GA has substantially reduced (p ≤ 0.001) insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and serum interleukin (IL)-6 in HFD-treated females. The results emphasize that GA can improve the hypothalamic antioxidative profile and insulin sensitivity along with glucose and lipid metabolism in progressive obesity. Graphical Abstract: Figure depicting the role of gallic acid against hypothalamic oxidative stress, insulin resistance, increased inflammatory marker, dyslipidemia, and diminished glucose tolerance caused by a high-fat diet. Symbol used:→ indicate increase and ↛ indicate suppression of activity. [Figure not available: see fulltext.] © 2023, The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.
