A Novel Aryl Hydrocarbon Receptor Antagonist HBU651 Ameliorates Peripheral and Hypothalamic Inflammation in High-Fat Diet-Induced Obese Mice

Abstract

Obesity is a chronic peripheral inflammation condition that is strongly correlated with neurodegenerative diseases and associated with exposure to environmental chemicals. The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear receptor activated by environmental chemical, such as dioxins, and also is a regulator of inflammation through interacting with nuclear factor (NF)-κB. In this study, we evaluated the anti-obesity and anti-inflammatory activity of HBU651, a novel AhR antagonist. In BV2 microglia cells, HBU651 successfully inhibited lipopolysaccharide (LPS)-mediated nuclear localization of NF-κB and production of NF-κB-dependent proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. It also restored LPS-induced mitochondrial dysfunction. While mice being fed a high-fat diet (HFD) induced peripheral and central inflammation and obesity, HBU651 alleviated HFD-induced obesity, insulin resistance, glucose intolerance, dyslipidemia, and liver enzyme activity, without hepatic and renal damage. HBU651 ameliorated the production of inflammatory cytokines and chemokines, proinflammatory Ly6chigh monocytes, and macrophage infiltration in the blood, liver, and adipose tissue. HBU651 also decreased microglial activation in the arcuate nucleus in the hypothalamus. These findings suggest that HBU651 may be a potential candidate for the treatment of obesity-related metabolic diseases.

Neuroprotective Effects of Aldehyde-Reducing Composition in an LPS-Induced Neuroinflammation Model of Parkinson’s Disease

“…Peripheral tissues, including the liver, have been studied as potential sources of biomarkers or insights into PD with the idea that changes in peripheral tissues may reflect systemic alterations associated with PD. We have reported that the mRNA levels of antioxidative enzymes and cytokines in the liver can reflect the systemic status of oxidative stress and inflammation in the mouse model [44]. In this study, we used the liver mRNA levels of inflammatory cytokines as an indirect indicator of systemic inflammation because serum inflammatory cytokine levels were changed similarly to hepatic cytokines [44].…”

“…We have reported that the mRNA levels of antioxidative enzymes and cytokines in the liver can reflect the systemic status of oxidative stress and inflammation in the mouse model [44]. In this study, we used the liver mRNA levels of inflammatory cytokines as an indirect indicator of systemic inflammation because serum inflammatory cytokine levels were changed similarly to hepatic cytokines [44]. However, the relationship between liver and brain tissues in terms of the mRNA expression of specific genes in PD is complex and not fully understood.…”

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…HBU651 is a novel synthetic AhR antagonist developed primarily for cancer which appears to be a suitable candidate for SCZ [213].…”

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…Recombinant interleukin-22 (IL-22) is a pleiotropic cytokine known for facilitating tissue regeneration and protecting the GI tract barrier. Recombinant IL-22, comprising two molecules connected by a fusion protein, exerts better efficacy with reduced systemic side effects [ 223 ].…”