107-OR: Brain GLP-1R Is Likely Required for Peripheral Liraglutide Treatment on Stimulating Hepatic FGF21

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are therapeutic agents for Type 2 Diabetes (T2D) and chronic weight management. We reported previously that peripheral GLP-1RA (liraglutide, Lira) administration stimulates hepatic fibroblast growth factor 21 (FGF21) in wild type but not GLP-1R^-/- mice, and GLP-1R is not expressed in the liver tissue. Here we aim to determine the underlying mechanisms for such stimulatory effect via organ-organ communications. Firstly, we asked whether acute intraduodenal (i.d.) GLP-1RA administration stimulates hepatic FGF21; and if so, whether the stimulation requires GLP-1R. We revealed that i.d. administration of GLP-1RA in WT mice significantly elevated hepatic Fgf21 levels by 5-fold compared to WT mice received i.d. PBS, whereas such effect was virtually lost in GLP-1R^-/- mice. Secondly, we investigated the central role of GLP-1R. We antagonized brain GLP-1R activity via i.c.v. Ex9-39 injection after peripheral Lira treatment in HFD-challenged mice. Mice received peripheral Lira treatment and i.c.v. Exendin 9-39 treatment show impaired stimulatory effect on serum FGF21 compared to the i.c.v. PBS counterpart, suggesting that brain GLP-1R is likely required for peripheral GLP-1RA to stimulate hepatic FGF21. Together, we further demonstrated that peripheral GLP-1RA administration stimulates hepatic FGF21, and revealed that such beneficial effect likely requires brain GLP-1R. Our study will aid the understanding of metabolic hormones and pave the way for determining their underlying mechanisms in metabolic homeostasis