Sex-dependent brain-specific alterations of insulin signalling uncover early molecular mechanisms leading to cognitive decline

Background: Insulin resistance is one of the most critical aspects of obesity and diabetes found to be tightly associated with increased oxidative stress, neurodegeneration, and cognitive decline. Intriguingly, brain insulin resistance appears earlier than other alterations. Men exhibit a higher vulnerability to western diet-induced insulin resistance, cognitive impairment and dementia when compared to women, particularly at a young age. However, the mechanisms behind these differences are still unclear. Hence, we aimed at characterizing early alterations of brain insulin signaling to uncover gender-differences that may be target of future investigations. Methods: C57BL/6J male and female mice were fed with a chow diet (CD, n=10/sex/group) or a high fat diet (HFD, 60% kcal by fat, n=10/sex/group) – this latter known to promote brain insulin resistance – for 1, 3 and 8 weeks. Peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tests (NOR and Y-maze) were performed. Insulin signaling activation and oxidative stress markers levels in the hippocampus, cortex and liver were evaluated. Collected data were further correlated with peripheral metabolic measurements and cognitive tasks outcomes. Results: HFD led to an altered glucose/insulin metabolism at each time point. Behavioral analyses show that male perform worse than female mice, and already after 1w of HFD. Brain insulin signaling activation shows consistent differences that are region- and sex- specific. Male mice are more vulnerable to the effects of HFD on insulin signaling activation in the brain and this is even more evident after intranasal insulin administration. Moreover, significantly increased HNE and 3-NT levels in both hippocampus and cortex from male mice can be observed as early as 1 w of HFD and correlates with insulin signaling alterations. Conclusion: Our data uncover sex-dependent and brain-specific alterations that uncover peculiar molecular mechanisms behind brain insulin resistance development and that are associated with cognitive decline.