Sex‐dependent effects of a high‐fat diet‐induced obesity model on cerebrovascular health and brain metabolism

Mid‐life obesity is a major risk factor for neurodegenerative diseases, with mitochondrial and cerebrovascular dysfunction considered key mediators. Lysine acetylation is a reversible post‐translational modification that regulates several mitochondrial metabolic and biochemical processes. The present study investigated the sex‐dependent effects of brain lysine acetylation and cerebrovascular and cognitive health in a high fat diet (HFD)‐induced obesity mouse model. We hypothesize that a HFD will cause an increase in acetylation, dysregulating mitochondrial respiration, potentially due to the decline in overall cerebrovascular health. Six‐month‐old C57/Bl6 mice (M/F) were placed on a 60% HFD or normal chow (CON) for 4 months. Changes in cerebral blood flux (CBF), behavioural testing, glucose tolerance testing and body composition were tested. Brain lysates were probed for various substrate utilizations, bioenergetics proteins and lysine acetylation. A HFD resulted in global metabolic dysregulation, with a substantial increase in weight and fat mass, with a greater increase in female mice; however, no cognitive changes were noted. Additionally, unlike female mice, males demonstrated a decrease in CBF after a HFD. Brain lysine acetylation was decreased in male HFD mice but increased in female HFD mice. Similarly, acetylation levels of fatty acid oxidation protein (long‐chain acyl‐CoA dehydrogenase), glucose oxidation proteins (pyruvate dehydrogenase, pyruvate carboxylase) and electron transport chain complex I (NDUFB8) and IV (MTCO1) proteins were decreased in male and increased in female brains after a HFD. In summary, our findings propose lysine acetylation as a novel and potential regulatory mechanism that impacts vascular and metabolic function in the brain mitochondria in a sex‐dependent manner.