High fructose corn syrup (HFCS) is a commonly used sweetener in soft drinks and processed foods, and HFCS exacerbates inflammation when consumed in excess. Fructose, a primary component of HFCS
however, it is unclear whether fructose directly activates inflammatory signaling. Growth hormone secretagogue receptor (GHSR) is a receptor of the nutrient-sensing hormone ghrelin. We previously reported that GHSR ablation mitigates HFCS-induced inflammation in adipose tissue and liver, shifting macrophages toward an anti-inflammatory spectrum. Since inflammation is primarily governed by innate immune cells, such as macrophages in the peripheral tissues and microglia in the brain, this study aims to investigate whether GHSR autonomously regulates pro-inflammatory activation in macrophages and microglia upon fructose exposure. GHSR deletion mutants of RAW 264.7 macrophages and the immortalized microglial cell line (IMG) were generated using CRISPR-Cas9 gene editing. After treating the cells with equimolar concentrations of fructose or glucose for 24 h, fructose increased mRNA and protein expression of GHSR and pro-inflammatory cytokines (Il1β, Il6, and Tnfα) in both macrophages and microglia, suggesting that fructose activates Ghsr and induces inflammation directly in macrophages and microglia. Remarkably, GHSR deletion mutants (Ghsr