High mobility group box-1 mediates hippocampal inflammation and contributes to cognitive deficits in high-fat high-fructose diet-induced obese rats

Abstract

High-fat high-sugar diet-induced obesity can lead to hippocampal inflammation and cognitive deficits, but the detailed underlying mechanism is still not clear. We aim to investigate the role of HMGB1 in hippocampal inflammatory responses and cognitive impairment in high-fat high-fructose diet (HFHFD)-induced obesity. Rats were fed with a normal control diet or an HFHFD diet for 14 weeks. In the last 6 weeks on the diets, the rats were treated with control, or an HMGB1 inhibitor glycyrrhizin, or an anti-HMGB1 neutralizing monoclonal antibody (mAb). Obesity was induced in the HFHFD-fed rats, which had higher body weight, epididymal white adipose tissue (EWAT) weight and caloric efficiency, and lower brain/body weight ratio, glucose tolerance and insulin sensitivity than the ones on normal diets. In the HFHFD-induced obese rats, the HMGB1 levels in plasma and hippocampus were increased, and the nucleus-to-cytoplasm translocation of HMGB1 was promoted. The hippocampal inflammatory responses were enhanced in the HFHFD-induced obesity, including the activation of TLR4 and NF-κB, the production of IL-1β, TNF-α and IL-6, as well as the activation of microglia and astrocytes. In addition, the hippocampal cell apoptosis and cognitive impairment were observed in the HFHFD-fed rats. The treatment with glycyrrhizin or HMGB1 mAb successfully decreased the HMGB1 levels in plasma and hippocampus, and prevented the HMGB1 translocation from the nucleus to cytoplasm. Inhibiting HMGB1 by glycyrrhizin or HMGB1 mAb suppressed the hippocampal inflammatory, alleviated the apoptosis and ameliorated the cognitive impairment in HFHFD-fed rats. These findings indicate that HMGB1 mediates the hippocampal inflammation and contributes to the cognitive deficits in HFHFD-induced obesity. Therefore, inhibition of HMGB1 may have beneficial effect in protecting against hippocampal inflammation and cognitive deficits in dietary obesity.

Keywords: Apoptosis; Astrocytes; Cognitive deficits; Diet; HMGB1; Inflammation; Microglia; Obesity.