Cardiometabolic Disease Promotes Sex-Specific Cognitive Decline

The detrimental effect of cardiometabolic disease (CMD) on metabolic health is well-established, and increasing evidence suggests a link between metabolic dysfunction and cognitive impairment, although the mechanisms remain unclear. Given that males often exhibit more pronounced adverse effects of CMD, evaluating sex differences is essential for understanding the varied cognitive outcomes associated with this condition. Therefore, our aim is to investigate the link between chronic HFD consumption and associated cognitive impairment in a sex-dependent manner. To test this hypothesis, male and female C57BL/6J mice (3 months old) were maintained on RD or HFD for the duration of the study (6 months). Initially, glucose tolerance testing (GTT) was conducted, followed by Y-maze behavioral assessment and laser speckle imaging to evaluate cerebral perfusion. At the end of the study, the mice were euthanized, and brains were collected for subsequent analyses. HFD-fed mice of both sexes showed a significant increase in body weight compared to RD-fed controls (n = 20; RD males: 33.20 ± 1 vs HFD males: 45.01 ± 1; RD females: 23.53 ± 1 vs HFD females: 33.80 ± 1; p < 0.0001, two-way ANOVA). GTT revealed slower normalization of blood glucose levels in HFD-fed males compared to HFD-fed females, indicating greater glucose intolerance in males (AUC: HFD males [46,023] vs HFD females [39,836]; p < 0.01, t-test). Cognitive performance assessed by Y-maze demonstrated that HFD-fed males exhibited significantly reduced spontaneous alternation percentage and correct alternation compared to RD-fed males (HFD males: 38.79 ± 3 vs RD males: 51.70 ± 4; p < 0.05). However, total arm entries did not differ, suggesting preserved locomotor function. In contrast, HFD-fed females performed similarly to RD-fed females in the Y-maze task but showed increased total arm entries (HFD females: 48.33 ± 5 vs RD females: 48.88 ± 6; p < 0.05). Laser speckle imaging showed significantly reduced cerebral perfusion in HFD mice compared to RD mice. Moreover, HFD males displayed the greatest perfusion deficit compared to RD males (HFD: 977.1 ± 31 vs RD: 1413 ± 35; p < 0.0001). HFD females showed milder reductions (HFD: 1109 ± 16 vs RD: 1666 ± 80; p < 0.0001). Thus, we conclude that chronic HFD consumption promotes metabolic dysfunction and impairs cognitive function in a sex-dependent manner, with males exhibiting greater glucose intolerance, reduced cerebral perfusion, and more pronounced cognitive deficits than females, highlighting a link between metabolic dysregulation and cognitive decline in CMD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.