Fructose induces inflammatory activation in macrophages and microglia through the nutrient-sensing ghrelin receptor.

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(mutant)) of macrophages and microglia exhibited reduced inflammatory responses to fructose, indicating that GHSR mediates fructose-induced inflammation. Furthermore, we found that GHSR regulates fructose transport and fructose metabolism and mediates fructose-induced inflammatory activation through CREB-AKT-NF-κB and p38 MAPK signaling pathways. Our results underscore that fructose triggers inflammation, and reducing HFCS consumption would reduce disease risk. Moreover, these findings reveal for the first time that the nutrient-sensing receptor GHSR plays a crucial role in fructose-mediated inflammatory activation, suggesting that targeting GHSR may be a promising therapeutic approach to combat the immunotoxicity of foods that contain fructose.