Blair Ellis, B.S.

@article{Le2022.04.21.489078,

title = {Glucagon-Like Peptide-1 Receptor Activation Stimulates PKA-Mediated Phosphorylation of Raptor and this Contributes to the Weight Loss Effect of Liraglutide},

author = {Thao D. V. Le and Dianxin Liu and Blair J. Ellis and Sheila Collins and Julio E. Ayala},

url = {https://www.biorxiv.org/content/early/2023/01/03/2022.04.21.489078},

doi = {10.1101/2022.04.21.489078},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {bioRxiv},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Objective The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide.Methods We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor.Results Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner. Liraglutide failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor. Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss.Conclusion GLP-1R agonists promote PKA-mediated phosphorylation of Raptor at Ser791, and this facilitates liraglutide-induced weight loss.Competing Interest StatementThe authors have declared no competing interest.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}