The short-chain fatty acid propionate exacerbates anxiety and cognitive deficits in high-fat diet-induced obese mice by impairing hippocampal neurogenesis and neuroinflammation

Abstract

Short-chain fatty acid propionate is a frequently used food preservative. However, excessive use of preservatives can pose environmental and public health risks. In addition, type 2 diabetes mellitus (T2DM) is a significant global public health concern. This study investigates whether propionate exposure affects the molecular mechanisms underlying the development of insulin resistance and neurobehavioral effects in high-fat diet mice. In this study, six-week-old male Balb/c mice were divided into four groups: standard diet (SD), propionate (15 mg/kg) (Pro), high-fat diet (HFD), and HFD supplemented with propionate (15 mg/kg) (HFD + Pro). After six weeks, the results indicated that exposure to HFD + Pro led to exacerbated weight gain, and fatty liver pathological changes, and affected glucose metabolism and insulin resistance compared to HFD mice. Furthermore, the HFD + Pro mice displayed heightened anxiety and depression behaviors in the elevated plus maze and forced swim tests, as well as cognitive and social impairments in the novel object recognition and social interaction tests. Additionally, HFD + Pro affects neuronal morphology and results in hippocampal loss, activates microglia, and leads to upregulation of neuroinflammatory factors IL-6 and IL-1β, and downregulation of IL-4 and IL-10. In conclusion, propionate exacerbates insulin resistance, impairs hippocampal neurogenesis and produces neuroinflammation, leading to behavioral deficits in HFD mice, this study provides evidence supporting the involvement of propionate in the pathogenesis of T2DM and brain neurobehavioral abnormalities. Further assessment of propionate safety is warranted.