The impact of a high-fat diet (HFD) on mouse behavior, neurotransmitters, inflammation, and gut-brain axis metabolism under hypoxic conditions

Abstract

In the context of the increasing global prevalence of mental health disorders, depression and anxiety have emerged as significant public health challenges. Notably, the incidence rates are higher in plateau regions. This study aimed to investigate the effects and underlying mechanisms of a high-fat diet (HFD) and hypoxic conditions on mouse behavior. The mice were subjected to different diets (a HFD or a normal diet) and placed in a hypoxic environment. This study explored relevant mechanisms through the measurement of physical and behavioral indicators, pathological assessments, biochemical analyses, evaluation of gut microbiota diversity, and metabolomics. The results indicated that a HFD induced obesity in mice under hypoxic conditions, leading to abnormal behavior and reduced synthesis of neurotransmitters such as 5-hydroxytryptaminergic (5-HT), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA). Additionally, a HFD may synergize with increased hypoxia-inducible factor (HIF) expression under hypoxic conditions, exacerbating multitissue inflammation, increasing proinflammatory factor levels, decreasing anti-inflammatory factor levels, and causing systemic inflammation due to gut injury, thereby damaging brain and gut tissues. Furthermore, a HFD altered the gut microbiota diversity, reducing beneficial bacteria while increasing harmful bacteria. KEGG pathway analysis and metabolomics revealed that the brain-gut metabolic pathway clustered around kynurenine metabolism, with metabolites such as kynurenic acid, 2-oxoadipic acid, (2-oxo-2,3-dihydro-1h-indol-3-yl) acetic acid, and D-kynurenine being reduced, which are associated with inflammatory and depressive/anxious behaviors. Subsequent Spearman correlation analysis revealed an interaction network among all factors, with kynurenic acid positioned at the core, serving as a key hub for interactions. Under dual stimulation from hypoxia and a HFD, this network becomes imbalanced, inducing cerebral and gut metabolic disorders and abnormal behaviors. This study elucidates the multifactorial mechanisms underlying abnormal behavior caused by a HFD and hypoxia in mice, providing a foundation for future research and prevention and treatment strategies for mental health disorders in plateau regions.