The Dopamine D2R Antagonist Trifluoperazine Suppresses High-Fat Diet-Induced Hyperglycemia and Hypothalamic Gliosis in Obese Mice

Microglia, the resident macrophages of the central nervous system (CNS), as well as astrocytes, are CNS glia cells to support neurodevelopment and neuronal function. Yet, their activation-associated with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in the obese individuals and animal models. Thus, reduction in peripheral and central inflammation is considered as a strategy to lessen the abnormality of obesity-associated metabolic indices. In this study, we reported that acute peripheral challenge by inflammagen lipopolysaccharide (LPS) triggered an upregulation of hypothalamic dopamine type 2 receptor (D2R) expression, and chronic feeding by high fat diet (HFD) caused an increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that a D2R antagonist named trifluoperazine (TFP) was able to suppress LPS-stimulated activation of microglia and effectively inhibited LPS-induced peripheral inflammation, as well as hypothalamic inflammation. Further findings showed daily peripheral administration intraperitoneally (i.p.) by TFP for 4 weeks was able to reduce the levels of plasma and hypothalamic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in obese mice receiving HFD for 16 weeks. Moreover, plasma glucose and insulin were effectively decreased by daily treatment with TFP for 4 weeks. In parallel, microglia and astrocytes in the ARC was also inhibited by peripheral administration by TFP. According to our results, TFP has the ability to suppress HFD-induced hyperglycemia, inflammation and gliosis in hypothalamus.