Metformin lowers glucose levels, appetite and body weight in rodents and humans, but the mechanisms on energy balance regulation have been rarely studied. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels in humans and rodents, while elevating GDF15 via GDF15 infusion in rodents lowers food intake and body weight via its receptor GDNF family receptor α-like (GFRAL) , which is expressed in the hindbrain nucleus area postrema (AP) . However, whether the GDF15-GFRAL axis in the AP mediates metformin effect is unknown. In this study, metformin (200 mg/kg) was infused into the upper small intestine (USI) of rats, while fasting-refeeding study or intravenous glucose tolerance test was performed. USI metformin infusion elevated plasma GDF15 levels (met 138 ± 25 vs. veh 59 ± 7 pg/ml, n = 8, p < 0.01) in parallel to a lowering of food intake (met 30 ± 2 vs. veh 40 ± 2 kcal, n = 16, p < 0.01) and an increase in glucose tolerance (AUC met 5243 ± 75 vs. veh 5674 ± 153, n = 7, p < 0.05) . Further, metformin lowered not only food intake but also body weight gain by 12 h (met 14 ± 1 vs. veh 23 ± 3 g, n = 8, p < 0.01) . Importantly, a knockdown of GFRAL achieved via an injection of lentivirus expressing shRNA GFRAL vs. mismatch into the AP by ∼40% (p < 0.05) negated the ability of metformin to not only lower food intake and body weight, but also increase glucose tolerance independent of body weight. Finally, acute AP GDF15 infusion (2 pmol) decreased food intake (GDF15-25 ± 2 vs. veh-36 ± 3 kcal, n = 10, p < 0.01) and weight gain (as early at 6 h, GDF15 3.6 ± 1.2 vs. vehicle 8.7 ± 1.6 g, n = 10, p < 0.05) , and increased glucose tolerance independently from body weight (AUC, GDF15-5322 ± 94 vs. veh-5722 ± 169, n = 6, p < 0.05) , and these metabolic effects of AP GDF15 infusion were prevented by GFRAL knockdown in the AP.
In summary, our findings indicate that the AP GDF15-GFRAL axis is sufficient and necessary for metformin to regulate energy and glucose homeostasis in rodents.
S.Zhang: None. R.Li: None. Z.Danaei: None. Y.Lim: None. T.K.Lam: None.
Canadian Institutes of Health Research (FDN-143204)