Brain region-specific disruption of mitochondrial bioenergetics in cynomolgus macaques fed a Western versus a Mediterranean diet.

Mitochondrial dysfunction is evident in diseases affecting cognition and metabolism such as Alzheimer's disease and type 2 diabetes. Human studies of brain mitochondrial function are limited to postmortem tissue, preventing the assessment of bioenergetics by respirometry. Here, we investigated the effect of two diets on mitochondrial bioenergetics in three brain regions: the prefrontal cortex (PFC), the entorhinal cortex (ERC), and the cerebellum (CB), using middle-aged nonhuman primates. Eighteen female cynomolgus macaques aged 12.3 ± 0.7 yr were fed either a Mediterranean diet that is associated with healthy outcomes or a Western diet that is associated with poor cognitive and metabolic outcomes. Average bioenergetic capacity within each brain region did not differ between diets. Distinct brain regions have different metabolic requirements related to their function and disease susceptibility. Therefore, we also examined differences in bioenergetic capacity between brain regions. Mitochondria isolated from animals fed a Mediterranean diet maintained distinct differences in mitochondrial bioenergetics between brain regions, whereas animals fed the Western diet had diminished distinction in bioenergetics between brain regions. Notably, fatty acid β-oxidation was not affected between regions in animals fed a Western diet. In addition, bioenergetics in animals fed a Western diet had positive associations with fasting blood glucose and insulin levels in PFC and ERC mitochondria but not in CB mitochondria. Altogether, these data indicate that a Western diet disrupts bioenergetic patterns across brain regions and that circulating blood glucose and insulin levels in Western-diet fed animals influence bioenergetics in brain regions susceptible to Alzheimer's disease and type 2 diabetes. We show that compared with cynomolgus macaques fed a Mediterranean diet, a Western diet resulted in diminished bioenergetic pattern between brain regions related to blood glucose and insulin levels, specifically in brain regions susceptible to neurodegeneration and diabetes. In addition, fatty acid metabolism not directly linked to the TCA cycle and glucose metabolism did not show differences in bioenergetics due to diet.