Prevention of Metabolic Impairment by Dietary Nitrate in Overweight Male Mice Improves Stroke Outcome

Background/objectives: Overweight increases the predisposition to obesity and type 2 diabetes (T2D), which significantly elevate stroke risk and the likelihood of severe post-stroke disability. However, since overweight itself is not a disease, interventions to prevent its progression to obesity/T2D comprise predominantly generic lifestyle recommendations that often lack long-term adherence. Dietary nitrate (NO) supplementation can mitigate obesity and metabolic impairments, making it a promising, non-pharmacological approach to halt overweight from progressing into obesity/T2D, thereby potentially also improving stroke outcome. We determined whether NO- supplementation prevents overweight from progressing into obesity and T2D and whether this intervention improves stroke outcome. Methods: Overweight was induced via 6 weeks of high-fat diet (HFD), after which animals were randomized to either HFD or HFD and NO-supplementation. After 24 weeks, when HFD-mice without NO developed obesity and T2D, all animals were subjected to transient middle cerebral artery occlusion and stroke outcome was assessed via behavioral testing and infarct size. The effect of NO on post-stroke neuroinflammation, neurogenesis, and neovascularization was analyzed by immunohistochemistry. Results: Sustained NO-supplementation in overweight mice did not prevent obesity or insulin resistance. However, it attenuated weight gain, prevented hyperglycemia and significantly improved functional recovery after stroke, without affecting infarct size. Moreover, NO decreased post-stroke neuroinflammation, but did not affect stroke-induced neurogenesis or vascularization. Conclusion: These results highlight the potential of NO-supplementation to prevent metabolic impairment in the overweight population and improve stroke prognosis in this large group of people at risk of stroke and severe stroke sequelae.