Exercise-induced weight loss modulates brain iron and Omega-3 fatty acid metabolism in middle-aged obese rats

Objectives: Midlife is a critical period for the onset of obesity and cognitive decline, which are often linked to disorders of iron and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). The aim was to investigate the effects of treadmill exercise on brain iron and LCPUFA metabolism. Methods: Middle-aged male rats were fed either a control diet or a 50% high-fat diet (HFD), with or without iron enrichment (2 g ferric iron/kg diet), for 8 weeks to induce dysmetabolic iron overload syndrome (DIOS). This was followed by 4 weeks of a hypocaloric diet and treadmill aerobic exercise (3 kcal/g of diet, 9.4% fat, 37 mg iron/kg of diet), and 1 week of behavioral testing. Hippocampal LCPUFA profiles were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Results: Consumption of an HFD significantly reduced hippocampal omega-3 LCPUFAs, with a further reduction in the DIOS group following the exercise intervention (p for trend < 0.001). A Western blot analysis showed that exercise/hypocaloric diet-mediated weight loss restored brain iron and LCPUFA metabolism by enhancing proteins involved in iron efflux (ferroportin), LCPUFA biogenesis (desaturases and elongase), phospholipid remodeling (acyl-CoA synthase long-chain family member and lysophosphatidyl choline acyltransferase), and neurotrophins (brain-derived neuro trophic factor), while reducing β-amyloid (all p < 0.05). The intervention restored cognitive function, although this effect was more pronounced in middle-aged obese rats without DIOS. Conclusions: These findings suggest that while exercise-induced weight loss supports brain health, additional strategies may be needed to address iron-related challenges in DIOS for optimal cognitive outcomes.