Abstract
Microglia and astrocytes are the glial cells of the central nervous system (CNS) to support neurodevelopment and neuronal function. Yet, their activation in association with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called as gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in 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) upregulated the expression of hypothalamic dopamine type 2 receptor (D2R) mRNA, and chronic feeding by high-fat-diet (HFD) significantly caused increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that an FDA-approved antipsychotic drug named trifluoperazine (TFP), a D2R inhibitor 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 tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in accompany with lower levels of plasma glucose and insulin in obese mice receiving HFD for 16 weeks when compared those in obese mice without TFP treatment. In parallel, the activation of 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 ARC gliosis and inflammation in the hypothalamus.
Highlights
Obesity caused by excessive dietary intake is a causal factor in the development of cardiovascular disease and a harmful stimulus to induce neurodegeneration in the central nervous system (CNS) and cognitive dysfunction (Miller and Spencer, 2014)
A reactive change in astrocytes (CNS supporting cell population) and microglia (CNS resident macrophages), occurs in the hypothalamus of obese rodents and humans (Thaler et al, 2012; Baufeld et al, 2016; Cai and Khor, 2019), which is considered as the cellular contributors of obesity-associated hypothalamic inflammation (Lee et al, 2020)
We found that inducible nitric oxide synthase (iNOS)+-microglia in the culture only treated with LPS displayed an amoeboid shape (Figure 1A, arrowheads), whereas microglia co-treated with LPS and TFP had a strong isolectin B4 (IB4) staining, and exhibited extending cell processes (Figure 1A, arrows)
Summary
Obesity caused by excessive dietary intake is a causal factor in the development of cardiovascular disease and a harmful stimulus to induce neurodegeneration in the central nervous system (CNS) and cognitive dysfunction (Miller and Spencer, 2014). A reactive change in astrocytes (CNS supporting cell population) and microglia (CNS resident macrophages), occurs in the hypothalamus of obese rodents and humans (Thaler et al, 2012; Baufeld et al, 2016; Cai and Khor, 2019), which is considered as the cellular contributors of obesity-associated hypothalamic inflammation (Lee et al, 2020). Since ARC is adjacent to the median eminence, a circumventricular organ that lacks the effective blood-brain barrier (Williams, 2012; Miller and Spencer, 2014), HFD-induced peripheral inflammatory regulators or free fatty acids are more permeable into this region, activate ARC glial cells, and initiate hypothalamic inflammation(Guillemot-Legris and Muccioli, 2017; Cai and Khor, 2019). The inhibition of hypothalamic inflammation is considered an effective strategy for the control of glucose homeostasis (Milanski et al, 2009; Miller and Spencer, 2014)
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