The activation of GPR FFA signaling triggers the PLC PIP

The activation of GPR40/FFA1 signaling triggers the PLC/PIP2 signaling pathway and results in Ca2+ release from the endoplasmic reticulum (ER). Increased Ca2+ levels may lead to activation of different protein kinases, such as Ca2+/calmodulin-dependent protein kinase type IV, Akt, extracellular signal-regulated kinase and mitogen-activated protein kinase, which phosphorylate CREB (Yamashima, 2012, Zamarbide et al., 2014). It is thought that PC2 activity or expression requires calcium. Our present findings suggest that supraspinal GPR40/FFA1 signaling may regulate the production of POMC-derived active peptides, such as β-endorphin, or enhance the release of β-endorphin from presynaptic terminals of POMC neurons. GPR40/FFA1 signaling (activated by DHA or GW9508) may lead to Ca2+ influx, increasing β-endorphin release from nerve terminals. In addition, the small neuroendocrine protein 7B2, present in all neural and endocrine tissues, has been shown to be required for the successful maturation of cellular proPC2 to the active form (Helwig et al., 2011). Recent work has shown that 7B2 blocks the aggregation of proPC2 into unactivatable forms (Lee and Lindberg, 2008). This suggests that GPR40/FFA1 signaling may increase PC2 protein expression by activating 7B2. In inflammatory pain, PC2 protein expression is upregulated in the hypothalamus; however, the underlying mechanisms remain unclear. In our previous study, we demonstrated that pretreatment with GW1100 exacerbates formalin induced pain behavior (Nakamoto et al., 2015). Furthermore, we showed that free fatty AT9283 levels rise in the hypothalamus during inflammatory pain induced by CFA (Nakamoto et al., 2013), suggesting that free fatty acids may be continuously released during pain. The activation of GPR40/FFA1 receptor signaling by increased levels of endogenous polyunsaturated fatty acids may help in the suppression of pain behavior. In the present study, we found that PC2 protein expression in the hypothalamus gradually increased after CFA injection in a GW1100-dependent manner, suggesting that GW1100-induced exacerbation of pain behavior may be mediated by suppression of PC2 protein expression. Collectively, our findings suggest that, following a nociceptive stimulus, the GPR40/FFA1 receptor, activated by elevated levels of endogenous free fatty acids, may play a key role in the regulation of the endogenous pain control system.
Acknowledgment This work was supported by a Grant-in-Aid for Scientific Research (C) (24592364) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Type 2 diabetes mellitus (T2DM) is a serious metabolic disorder characterized by insulin resistance and insufficient insulin secretion from the pancreas. According to the global prevalence report from the IDF (International Diabetes Federation), there are about 415 million diabetics worldwide in 2015 with T2DM comprising over 80% of the cases . The pharmacotherapy for T2DM realizes the glycemic control by increasing the body’s sensitivity to insulin, enhancing insulin secretion and reducing renal glucose reabsorption. Though a range of anti-diabetic drugs with different modes of action have been launched, most of them are associated with adverse effects, such as hypoglycemia, intestinal discomfort, edema, increased fracture risk and so on . The development of effective and highly safe anti-diabetic agents still remains a significant need for the rapidly increasing diabetic population. Recently, along with the successful launch of GLP-1 analogues and DPP4 inhibitors, intensive interest in the development of T2DM therapeutics has been stimulated on the targets which enhance insulin secretion in a glucose-dependent manner thereby minimizing the risk of hypoglycemia . GPR40 is such a viable and promising therapeutic target that have attracted global pharmaceutical industry and academia to develop new oral antidiabetic drugs acting on this receptor. Nowadays, a number of synthetic potent GPR40 agonists have been reported and the most advanced compound was from which was once in phase III clinical trials, providing proof-of-concept for this approach .