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.

Article Highlights
  • In rodents fed a high-fat diet (HFD), GDF15 decreases feeding and weight while increasing energy expenditure, glucose tolerance, and insulin sensitivity via its receptor, GFRAL, which is expressed in the area postrema.

  • In HFD rats, we investigated the role of the GDF15–GFRAL axis within the area postrema in glucose regulation independent of weight.

  • We found that GDF15 infusion into the area postrema increases glucose tolerance and insulin sensitivity, and a knock down of GFRAL in the area postrema negates GDF15 or metformin to increase glucose tolerance.

  • Our study indicates that the GDF15–GFRAL axis increases glucose tolerance independent of weight and contributes to the metformin glucoregulatory action.

S.-Y.Z. and Z.D. contributed equally to this work.

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