Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic multisystem disease affecting approximately 30% of the general population and more than 80% of individuals with obesity. It frequently coexists with cardiovascular disease, diabetes, and cancer, contributing to a growing global burden of multimorbidity. While hepatic encephalopathy is classically associated with advanced liver disease, accumulating evidence indicates that neurocognitive impairment and accelerated brain ageing also occur in earlier stages of MASLD. However, the mechanisms driving these cerebral alterations, and whether they are reversible following disease resolution, remain largely unknown.

In this talk, data will be presented from male C57BL/6NTac mice fed a control diet (CD) or a high-fat, high-cholesterol diet (HFD) for 26 weeks to induce MASLD. To assess the impact of ageing and dietary intervention, a subset of HFD-fed mice was subsequently switched to a low-fat diet (LFD) and followed until 18 months of age. All animal procedures were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and its associated guidelines, and complied with the ARRIVE guidelines. The study was conducted under a UK Home Office Project Licence and approved by the local Animal Welfare and Ethical Review Body (AWERB). All efforts were made to minimise animal suffering and to reduce the number of animals used.

Behavioural analyses revealed anxiety-like behaviour in both HFD and aged HFD-LFD mice, while memory impairment was evident in aged CD-LFD and HFD-LFD groups.Measurements of brain oxygenation showed reduced partial pressure of oxygen and tissue oxygen saturation in HFD, aged HFD-LFD, and CD-LFD mice at baseline, assessed under anaesthesia using fluorescence-based methods and optoacoustic tomography. Cerebrovascular reactivity to systemic hypercapnia (10% CO₂) was preserved. Structural analyses demonstrated altered vascular complexity and reduced pericyte coverage in HFD and aged HFD-LFD mice compared to controls. These changes were accompanied by increased cortical microglial density, coverage, and volume, consistent with a reactive inflammatory phenotype.

Together, these findings identify altered brain oxygenation and inflammation as potential contributors to MASLD-associated brain dysfunction. Importantly, dietary fat reduction in later life did not reverse MASLD or its associated cerebral alterations, suggesting that brain vulnerability may persist or even be exacerbated with ageing. Ongoing studies in mice of both sexes are currently exploring alternative dietary strategies and mechanisms acting along the gut-liver–brain axis. This work aims to define the long-term impact of MASLD on brain health, even after liver disease improvement, and to understand how metabolic liver disease interacts with the natural ageing process.