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

Background/objectives: Being overweight increases the predisposition to obesity and type 2 diabetes (T2D), which significantly elevate stroke risk and the likelihood of severe post-stroke disability. Dietary nitrate (NO3−) supplementation can mitigate obesity and metabolic impairments, making it a promising approach to halt overweight people from developing overt obesity/T2D, thereby potentially also improving stroke outcome. We determined whether NO3− supplementation prevents overweight mice from progressing into obesity and T2D and whether this intervention improves stroke outcome. Methods: An overweight condition was induced via 6 weeks of a high-fat diet (HFD), after which animals were randomized to either a HFD or a HFD with NO3− supplementation. After 24 weeks, when HFD-mice without NO3− 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 NO3− on post-stroke neuroinflammation, neurogenesis, and neovascularization was analyzed by immunohistochemistry. Results: Sustained NO3− 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, NO3− decreased post-stroke neuroinflammation by reducing microglial infiltration. NO3− did not affect stroke-induced neurogenesis or vascularization. Conclusion: These results highlight the potential of NO3− 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.