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    • It is considered that activations of MMP and MMP are

    2021-10-25

    It is considered that activations of MMP-2 and MMP-9 are closely related to progression process of cancer cells, such as invasion and metastasis [22], [23]. In fibrosarcoma cells, GPR40 suppressed not only MMP-2 and MMP-9 activations, but also cell motile and invasive activities, suggesting GPR40 negatively regulates cellular functions of fibrosarcoma KPT-276 synthesis [11]. The present study showed that MMP-9 activation induced by the long-term TPA treatment was inhibited by GPR120 knockdown. Therefore, these findings demonstrated that GPR40 enhanced the cell motile activity of A375 cells treated with TPA, whereas activity level of MMP-9 was inhibited by GPR40. In conclusion, GPR120 inhibits and GPR40 enhances the cell motile activity stimulated by TPA in melanoma cells, while MMP-9 activation was reduced by GPR40. In contrast, GPR40 negatively regulated cellular functions of fibrosarcoma cells [11]. Taken together, it is suggested that opposite effects of GPR120 and GPR40 are involved in the regulation of cellular functions, dependent on types of cells. We are currently investigating whether GPR120 and GPR40 may contribute to acquisition of chemo-resistance in melanoma cells.
    Conflict of interest statement
    Acknowledgements This work was supported by JSPS KAKENHI Grant Number 24590493 and by Grants from the Faculty of Science and Engineering, Kindai University.
    Introduction Type 2 diabetes (T2D) is a global epidemic (International Diabetes Federation, 2013) characterized by hyperglycemia due to impaired islet function and insulin resistance in peripheral tissues. Despite advances in understanding the molecular mechanisms contributing to T2D and the development of new treatment modalities, the medical management of T2D remains inadequate (Aroda et al., 2012). At present, many available treatment strategies including analogs of the incretin, glucagon-like peptide 1 (GLP-1), and dipeptidylpeptidase-4 inhibitors work primarily by increasing insulin secretion. Other effective agents promote glucose excretion (Campbell and Drucker, 2013, Meier, 2012). However, there is still a need for effective and safe agents that enhance insulin sensitivity to improve glucose control and prevent diabetic complications. We discovered a novel class of endogenous lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), with beneficial metabolic and anti-inflammatory effects (Yore et al., 2014). More than 16 FAHFA family members have been identified (Yore et al., 2014, Ma et al., 2015). Levels of one of the FAHFA family members, palmitic acid hydroxystearic acid (PAHSA), are markedly lower in serum and adipose tissue (AT) of insulin-resistant humans. PAHSA levels correlate strongly with insulin sensitivity as measured by euglycemic clamps in humans (Yore et al., 2014). Acute oral treatment with 5- or 9-PAHSA isomer in chow-fed and high-fat diet (HFD)-fed mice improves glucose tolerance and augments insulin and GLP-1 secretion in vivo. In vitro, PAHSAs directly enhance GLP-1 secretion from enteroendocrine cells and glucose-stimulated insulin secretion (GSIS) from human islets (Yore et al., 2014). Furthermore, PAHSAs have anti-inflammatory effects including decreasing AT inflammation in HFD mice and attenuating lipopolysaccharide-induced dendritic cell activation and cytokine production. Although we reported that a single dose of PAHSAs acutely improves glucose tolerance, whether PAHSAs have effects on insulin sensitivity has not been investigated. Therefore, the first aim of this study was to determine whether PAHSA treatment enhances insulin sensitivity in vivo, and the second aim was to determine whether the beneficial effects of PAHSAs are sustained with chronic treatment. The receptors responsible for PAHSA effects on insulin secretion and insulin action in vivo have not been identified. The G protein-coupled receptor (GPCR) GPR120 mediates PAHSA effects to enhance insulin-stimulated glucose transport in adipocytes (Yore et al., 2014), but PAHSAs are likely to activate other GPCRs because of their diverse actions in multiple tissues. Major pharmaceutical companies have had high-priority programs to screen for GPR120 and GPR40 activators to treat T2D. Molecules that activate both of these GPCRs with naturally evolved relative affinities may be more effective for T2D treatment than agonists for single receptors.