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Glucagon-like peptide 1 receptor (GLP-1R) agonists enhance glucose-stimulated insulin secretion and act on several regions of the brain to reduce food intake and body weight, making the GLP-1R a major therapeutic target for the treatment of type 2 diabetes and obesity. Surprisingly, little is known about the signaling mechanisms mediating the food intake-lowering effects of GLP-1R agonists. We have previously shown that inhibiting the mechanistic Target of Rapamycin (mTOR) in the ventromedial hypothalamus blocks anorexia induced by GLP-1R activation in this brain nucleus (1). Therefore, the goal of the present studies is to elucidate the mechanisms by which GLP-1R activation stimulates mTOR signaling. To accomplish this, we treated Chinese Hamster Ovary cells stably expressing the human GLP-1R with the GLP-1R agonist liraglutide (Lira) in combination with inhibitors of various signaling molecules. Since PKA is a canonical target of GLP-1R signaling, and PKA phosphorylates mTOR and its regulating protein Raptor following β-adrenergic stimulation (2), we used the PKA inhibitors H89 and KT 5720 to examine whether PKA is required for the stimulation of mTOR activity by Lira. We expressed myc-tagged mTOR or Raptor in GLP-1R stably expressing CHO cells, treated them with Lira, immunoprecipitated myc-mTOR or myc-Raptor, and immunoblotted for the PKA substrate RRXS/T motif. We found that Lira significantly increased PKA-substrate motif phosphorylation of myc-Raptor but not myc-mTOR, and this was blocked by pre-treatment with H89. Lira also failed to stimulate phosphorylation of a Ser791Ala Raptor mutant that cannot be phosphorylated by PKA (2). To test whether Akt, a well-known regulator of mTOR activity, contributes to the activation of mTOR signaling by Lira, we pre-treated GLP-1R stably expressing CHO cells with either of the Akt inhibitors Akt-i 1/2 and MK-2206 followed by treatment with Lira or forskolin (Fsk), a cAMP inducer and PKA activator. Pre-treatment with either Akt-i 1/2 or MK-2206 blocked mTOR activation by both Lira and Fsk. This suggests that the contribution of Akt to Lira-induced mTOR activation is likely downstream of cAMP production. Taken together, our results suggest a novel two-pronged, PKA-dependent mechanism for the stimulation of mTOR signaling following GLP-1R activation – directly via phosphorylation of Raptor and indirectly via stimulation of Akt. Future studies will assess the respective contributions and temporal dynamics of each of these pathways. Reference: (1) Burmeister et al., Am J Physiol Endocrinol Metab. 2017 Aug;313: E651–E662. (2) Liu et al., J Clin Invest. 2016;126(5):1704-1716.

The Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Stimulates Mechanistic Target of Rapamycin (mTOR) Signaling via PKA And Akt