Therapeutic application of GPR119 ligands in metabolic disorders

Abstract

GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

“…We then assessed the effect of OEA (endogenous GPR119 ligand) on proliferation of MCF-7 cells. Because EC 50 values of MBX-2982 and OEA for GPR119 are 3.9 nM and 0.2–5 μM, respectively [ 22 ], pharmacological potency of MBX-2982 is 51.3–1282.1 fold higher than OEA. When we assessed cell proliferation inhibitory effect of OEA (10 mM) in MCF-7 cells, the compound did not change the basal cell growth (Additional file 1 : Figure S1D).…”

“…We previously reported that MBX-2982 activated AMP-activated protein kinase (AMPK), and pleiotrophic roles of AMPK have been investigated in many types of cancer [ 22 , 29 ]. Hence, we further investigated a potential role of AMPK in autophagy inhibition by GPR119 agonist.…”

The effects of oleoylethanolamide, an endogenous PPAR‐α agonist, on risk factors for NAFLD: A systematic review

“…In this context, Lauffer et al showed that OEA administration (10 μmol/L) stimulated GPR119, a G protein‐coupled receptor, in ileum L‐cells to secrete GLP‐1, a gut hormone that delays gastric emptying and exerts anorectic effects, in the mouse GLUTag cell line. Yang et al demonstrated that the activation of GPR119 induced the phosphorylation and activation of AMP‐activated protein kinase (AMPK) and thereby inhibited the expression of sterol regulatory element‐binding protein‐1 (SREBP‐1) in hepatocytes. The downregulation of SREBP‐1 decreased lipogenic enzyme gene expression, including acetyl‐CoA carboxylase (ACC), fatty acid synthase (FAS), and SCD1, resulting in a reduction in hepatic lipid accumulation …”

“…GPR119 is considered part of the ECS . In patients with NAFLD, the hepatic expression of CB1R/CB2R and the serum levels of the endocannabinoid 2‐AG were increased .…”

“…As mentioned above, OEA exerts its effects both via its major binding partner PPAR‐α and other receptors such as TRPV1 and GRP119. Because of that, physiological functions of OEA are more diverse than that of other PPAR‐α agonists such as Wy‐14643 and fenofibrate . In the MCD model of liver disease, Wy‐1464 reduced steatohepatitis and liver fibrosis; nevertheless, Wy‐1464 was not effective in diminishing the expression of enhanced TGF‐β1 transcription factor .…”