Abstract
The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.
Highlights
For calcium mobilization and dynamic mass redistribution (DMR) assays compounds were prediluted in Hanksbuffered saline solution (HBSS), 20 mM HEPES and 0.01% bovine serum albumin (BSA) (1% DMSO)
We found that the compound significantly increased the acute insulin secretion in the wt mice compared to the vehicle group (p
GPR120, which is expressed in both islet and in enteroendocrine cells, is activated by mediumand long-chain fatty acids (LCFAs) and has been extensively investigated as a drug target for treatment of obesity and type 2 diabetes due to its many effects on metabolism including increasing secretion of glucagon-like peptide-1 (GLP-1) [28, 29]
Summary
The funder provided support in the form of salaries for all authors [LS, SM, MS, AA, WM, PR, SDG, MP, CAN, LK, MN, MSW], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The major reasons for this is likely unhealthy diet and lifestyle choices leading to obesity, insulin resistance and elevated levels of free fatty acids in plasma [2]. Free fatty acids are categorized as short, medium, long and very long-chain, all of which can act as signaling molecules for a group of G-protein coupled receptors (GPCRs) consisting of GPR40, GPR41, GPR43, GPR84 and GPR120 [3,4,5,6,7].
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