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  • In normal tissues the expression


    In normal tissues, the expression patterns of GPR120 and GPR40 are not uniform. GPR120 is highly expressed in adipocytes, lung and intestinal tract, while GPR40 is shown to be expressed in pancreatic islet carnitine palmitoyltransferase and intestinal tract [7], [20]. It is considered that the distribution of the GPR120 and GPR40 expressions may be closely related to energy homeostasis, such as metabolism and immune process [7], [21]. In normal liver tissues, Gpr120 and Gpr40 genes were well expressed. In addition, the expression levels of the Gpr120 and Gpr40 genes were significantly elevated by the feeding of ethionine in rat livers. Based on these results, we generated the long-term ethionine treated cells and measured the expression levels of the Gpr120 and Gpr40 genes and the cell motile activity. The expression levels of the Gpr120 and Gpr40 genes were increased and the cell motile activity was enhanced by the long-term ethionine treatment, similar to the case for the short-term ethionine treamtment. Since ethionine is one of liver carcinogens, the roles of GPR120 and GPR40 in the development of liver tumors induced by ethionine in rats should be further clarified. In conclusion, we demonstrated that the diverse roles of GPR120 and GPR40 are involved in the activation of cell motile activity induced by ethionine in WB-F344 cells. Recently, it has been reported that the high expression levels of GPR120 were found in colorectal cancers in comparison with adjacent noncancerous tissues. The cell motile activity and angiogenesis process were enhanced by the activation of GPR120 in colorectal carcinoma cells [22]. Taken together with these findings, it is possible that GPR120 and GPR40 may be novel chemopreventive targets for the establishment of anti-cancer therapy.
    Conflict of interest
    Acknowledgments This work was supported by JSPS KAKENHI Grant Number 24590493 and by Grants from the Faculty of Science and Engineering, Kinki University.
    Type 2 diabetes mellitus (T2DM), which affects over 300million people worldwide, is a condition in which reduced insulin production and increased insulin resistance and hepatic glucose production result in hyperglycemia . Complications from T2DM include (but are not limited to) blindness, renal failure, amputations and cardiovascular disease . T2DM is a growing worldwide epidemic, and it is estimated that the number of people with T2DM will increase to 0.5billion by 2030 . In addition, many of today’s T2DM drugs often fail to demonstrate durable effects, with over half of medications failing to retain efficacy after five years . Given the role of insulin resistance in the pathophysiology of T2DM, novel therapies which lead to enhanced insulin sensitivity are highly desirable. With this in mind, we became interested in targeting the G protein-coupled receptor 120 (GPR120). GPR120, encoded by the free fatty acid receptor 4 (FFAR4) gene, is highly expressed in the intestines, pancreatic islets, macrophages, and adipocytes . Stimulation of GPR120 by long chain free fatty acids has been shown to increase the secretion of GLP-1 in mice, which in turn leads to a glucose-dependent increase in insulin secretion . In addition, GPR120 stimulation with both fatty acids and a small molecule GPR120 agonist led to an improvement in insulin sensitivity in a rodent model . GPR120 agonists are therefore promising for the treatment of T2DM, insulin resistance and obesity-related disorders , , and we sought to identify additional structurally diverse chemical matter . As the glucose lowering effects of GPR40 (FFAR1) agonists are now well recognized, we aimed to further understand the effects of GPR120 activation. Consequently, we set out to identify GPR120 agonists displaying high selectivity over this closely related fatty acid receptor . An ultra high-throughput screen was used to identify potent, selective GPR120 compounds, with compound () emerging as a promising hit. Compound contains a benzisoxazole “left-hand” piece, a bis-chloro phenyl core and a butanoic acid “right-hand” piece. Although compound only demonstrated moderate potency in a GPR120 IP1-based functional assay , it possessed an attractive mouse PK profile and selectivity over GPR40. Our efforts to optimize the potency of compound are described herein.