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. 2025 Oct 3.
doi: 10.1113/EP093187. Online ahead of print.

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

Nicole N Eminhizer  1 , Dena Lin  1 , Alec Hanshew  1 , Jackson Stewart  1 , Steven Ball  1 , Christa Lilly  2 , Saina S Prabhu  3 , Kate Karelina  4 , Eric E Kelley  5 , Randy W Bryner  1 , Dharendra Thapa  1 , Paul D Chantler  1   4
Affiliations

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

Nicole N Eminhizer et al. Exp Physiol. .

Abstract

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.

Keywords: cerebrovascular health; lysine acetylation; obesity; sex dependent.

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References

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