Propionate Aggravates Anxiety and Cognitive Dysfunction in High-Fat Diet Mice by Activating Hippocampal Microglia-Mediated Neuroinflammation

Insulin resistance constitutes a major global public health burden, and obesity─a critical precursor of insulin resistance─is closely associated with comorbid anxiety, depressive disorders, and cognitive impairments. Propionate, a short-chain fatty acid (SCFA) and widely used food preservative, exhibits potential public health hazards at excessive concentrations; however, its effects on neuropsychiatric manifestations and the underlying mechanisms in high-fat diet (HFD)-induced metabolic dysfunction remain insufficiently investigated. Herein, we focused on the effects of propionate on neurobehavioral impairments in HFD-fed mice, as well as the associated metabolic and neural perturbations. Six-week-old male Balb/c mice were randomly divided into four groups for a 6-week intervention: standard diet (SD), propionate (15 mg/kg, Pro), HFD, and HFD combined with propionate (15 mg/kg, HFD+Pro). Relative to the HFD group, mice in the HFD+Pro group displayed exacerbated weight gain, fatty liver pathological changes, impaired glucose homeostasis, and aggravated insulin resistance. Behaviorally, exposure to HFD+Pro induced more severe anxiety-like and depressive-like phenotypes (assessed via the elevated plus maze and forced swim test) and exacerbated cognitive and social impairments (evaluated using the novel object recognition test and social interaction test). At the neural level, HFD+Pro treatment induced hippocampal neuronal loss, microglial activation, upregulation of the pro-inflammatory cytokines Il-6 and Il-1β, and downregulation of the anti-inflammatory cytokines Il-4 and Il-10. Collectively, propionate exacerbates HFD-induced neuroinflammation and hippocampal injury, which contributes to the onset and progression of comorbid neuropsychiatric impairments, while aggravating insulin resistance-associated metabolic disturbances. This study establishes a critical association between propionate exposure and insulin resistance-related neuropsychiatric pathology, highlighting the urgent need to reevaluate the safety profile of propionate in populations at risk.