Acute Activation of GFRAL in the Area Postrema Contributes to Glucose Regulation Independent of Weight

GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL, expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct, acute GDF15 infusion into the area postrema of rats fed a high-fat diet increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and nonstressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema negated administration of GDF15, as well as metformin, to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo.