Dietary nitrate and resveratrol co-supplementation prevent HFD-mediated impairments in carotid blood flow and behavioral parameters in male mice.

While dietary nitrate (NIT) and resveratrol (RSV) have known metabolic effects within peripheral tissues, their impact within the brain remains unknown. We investigated these compounds' independent and combined (+RN) efficacy in preserving brain blood flow, and their impact on mitochondrial bioenergetics and behavior in C57Bl/6N male mice consuming a high-fat diet (HFD; n = 100). Carotid blood flow was measured via ultrasonography, the cortex was permeabilized to determine mitochondrial function, and homogenized for analysis of various protein targets. Physical activity in a novel environment was evaluated as an index of habituation outcomes. HFD feeding reduced carotid blood flow and decreased cortical VEGF protein content (p = 0.057) but did not alter mitochondrial function. While RSV did not prevent HFD-induced declines in brain blood flow, NIT independently, and combined with resveratrol (+RN), preserved carotid blood flow (p < 0.02) and VEGF protein content. These indexes of brain blood flow coincided and correlated with reduced anxiety-like behavior. Despite the improved habituation, combined +RN supplementation reduced cortical mitochondrial respiration without altering mitochondrial ROS emission, redox balance, or markers of mitochondrial content/mitophagy. These findings suggest NIT may have beneficial effects within the brain through the maintenance of carotid blood flow, as opposed to alterations in mitochondrial bioenergetics within the cortex.