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    • However Gingrich and Hen reported that absence

    2022-06-24

    However, Gingrich and Hen reported that absence of the gene at all stages of ontogenesis of mice may interfere with the normal developmental program and/or the organism may undergo changes in other systems to compensate for gene absence (46). In addition, potentially altered maternal behavior of GPR40/FFAR1 KO dams might have a great impact on the resulting phenotype of adult KO offspring because of significant role of maternal behavior in the expression of a phenotype change in adult mice (47), (48). Therefore, we cannot excluded that obtained behavioral and physiological changes can be attributed to above-mentioned factors.
    Conflict of interest
    Acknowledgments This study was supported by 1) Grants-in-Aid and Special Coordination Funds from the Kobe Gakuin University Joint Research (A), 2) the Takeda Pharmaceutical Sciences and 3) a Grants-in-Aid for Scientific Research (C) (15K10566) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and the Takeda Science Foundation.
    Introduction Previously, we demonstrated that docosahexaenoic chk1 inhibitor (DHA) or GW9508, a GPR40/FFA1 (free fatty acid receptor 1) agonist, suppress formalin-induced pain behavior by increasing β-endorphin release from pro-opiomelanocortin (POMC) neurons in the hypothalamus in mice (Nakamoto et al., 2012, Nakamoto et al., 2013). In the arcuate nucleus, β-endorphin is rapidly released by pain stimuli (Young et al., 1993). Interestingly, we demonstrated increasing levels of free fatty acids in the hypothalamus during inflammatory pain induced by complete Freund's adjuvant (CFA), suggesting that free fatty acids may be continuously released during pain. These findings suggest that the activation of GPR40/FFA1 receptor signaling may contribute to pain control by regulating β-endorphin release. However, it remains unclear how GPR40/FFA1 signaling in the hypothalamus facilitates β-endorphin release. Prohormone convertases (PC) 1/3 and 2 in the hypothalamus and pituitary are members of a calcium-dependent, subtilisin-like serine protease family (Rouille et al., 1995, Seidah and Chretien, 1999). In PC2-null mice, POMC, proenkephalin and prodynorphin processing is reduced (Laurent et al., 2004, Phillips et al., 2000). PC2 is mainly involved in the production of the POMC-derived endogenous opioid peptide, β-endorphin (Benjannet et al., 1991, Laurent et al., 2004). GPR40/FFA1 is coupled to an intracellular G protein (Gq) that activates the phospholipase C (PLC) and phosphatidylinositol-4,5-bisphosphate (PIP2) signaling pathway (Briscoe et al., 2003). PLC activation, in particular, leads to Ca2+ influx in nerve terminals (Mancini and Poitout, 2013). Thus, we hypothesized that GPR40/FFA1 signaling may regulate PC2 protein expression.
    Materials and methods
    Results
    Discussion In this study, we demonstrated that GPR40/FFA1 agonist increases PC2 protein expression in the hypothalamus, suggesting that PC2 protein expression may be regulated by supraspinal GPR40/FFA1 signaling. Findings in our previous study suggested that GW9508-induced activation of brain GPR40/FFA1 receptor signaling produces antinociception via the production of β-endorphin by activating POMC neurons (Nakamoto et al., 2013). Generally, POMC is processed in a tissue-specific manner to yield biologically active peptides. POMC is initially cleaved by PC1/3 to generate pro-adrenocorticotropic hormone (ACTH) and β-lipotropin (LPH). Pro-ACTH is then cleaved by PC1/3 into ACTH and N-terminal POMC. Further processing by PC2 yields ACTH1–17 and β-endorphin1–31, as well as γ-LPH and CLIP. Thus, PC2 in the hypothalamus plays a critical role in the production of β-endorphin (Benjannet et al., 1991). In this study, PC2-positive cells in the hypothalamus co-express GPR40/FFA1 positive cells. There are many reports that POMC is post-translationally processed to yield a number of neuropeptides, including β-END. Originally identified as a product of the pituitary gland and the hypothalamus. Our previous study, we have demonstrated that GPR40/FFA1 protein was co-expressed on neuron containing POMC or β-END (Nakamoto et al., 2013). Based on our data, it is thought that the activation of GPR40/FFA1 signaling may regulate the process of β-END production in the arcuate neucleus of the hypothalamus. However, the mechanisms regulating PC2 protein expression remain unclear, and we cannot rule out whether the activation of GPR40/FFA1 signaling facilitates the process of exocytosis from neuron in this study.