Diet-induced MAFLD: Unraveling liver-brain axis alterations and therapeutic potential of combined OLHHA and liraglutide treatment

Metabolic Associated Fatty Liver Disease (MAFLD) has recently emerged as a major health concern in Western countries, being characterized by hepatic fat accumulation, altered metabolism, increased oxidative stress, and inflammation. This condition triggers the release of hormones, free radicals, and inflammatory mediators in blood, potentially affecting central nervous system. Unfortunately, limited studies have explored the impact of MAFLD on the brain and its potential association with neuronal metabolism and activity. In our study, we utilized preclinical MAFLD model induced by a six-week exposure to a high-fat high-fructose diet. Animals received treatments of a vehicle, liraglutide (24 ug/kg), OLHHA (5 mg/kg; a dual agonist/antagonist of PPARa/CB1 receptor), or a combination of both. Diet exposure alone resulted in altered plasma biochemical and inflammatory parameters, along with increased liver fat deposition and changes in gene expression related to metabolism, inflammation, and oxidative stress. Interestingly, the same animals exhibited alterations at the brain level in protein expression linked to the insulin pathway, inflammation, neurogenesis, and increased tau phosphorylation in cognitive areas such as medial prefrontal cortex and hippocampus. Significantly, the combined treatment of OLHHA and liraglutide effectively improved plasma biochemical and inflammatory parameters, mitigating liver alterations. Along with peripheral improvements, the combined treatment also restored the alterations noticed at the brain level, suggesting a potential interplay between metabolic dysregulation in the liver and neuronal dysfunction. In conclusion, our findings underscore the connection between metabolic disorders and brain function, highlighting the importance of addressing both peripheral and central aspects in the management of MAFLD.