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  • In conclusion this is the first description

    2021-09-13

    In conclusion, this is the first description of a GPR81 agonist with an ability to exert in vivo efficacy without causing flushing. These results demonstrate that GPR81 small-molecule agonists may be effective for treating dyslipidemia. In addition, targeting GPR81 could prevent the unwanted side effect, i.e., flushing, which has been a major problem associated with nicotinic acid.
    Acknowledgments
    Introduction Elevated plasma and tissue concentrations of non-esterified fatty acids (NEFA) and triglycerides are often observed in patients with type 2 diabetes mellitus (T2DM) (DeFronzo, 2004, Paolisso et al., 1995, Reaven and Greenfield, 1981) and are strongly associated with insulin resistance (Boden, 1997, Groop et al., 1989, Groop et al., 1991). Reduction of NEFA concentration in the circulation improves insulin sensitivity and β-cell function, thereby reducing the risk for diabetes (Bajaj et al., 2004, Bergman and Ader, 2000, Dobbins et al., 2013, Fulcher et al., 1992, Kumar et al., 1994, Randle et al., 1963, Worm et al., 1994). Suppression of lipolysis in the adipocytes by nicotinic Iodophenpropit dihydrobromide australia or its analogues acutely improves glucose handling and insulin sensitivity in subjects with T2DM (Bajaj et al., 2004, Dobbins et al., 2013, Fulcher et al., 1992, Kumar et al., 1994, Liang et al., 2013, Santomauro et al., 1999, Worm et al., 1994). This effect is mediated by the G-protein-coupled receptor 109A (GPR109A, also called HCAR2 (hydroxycarboxylic acid receptor 2), Fig. 1) (Soga et al., 2003, Tunaru et al., 2003, Wise et al., 2003). However, GPR109A activation is associated with cutaneous vasodilatation manifested as flushing, due to release of vasodilatory prostanoids from epidermal Langerhans cells (Benyó et al., 2006, Benyó et al., 2005, Kamanna et al., 2009). Furthermore, the mechanism by which GPR109A reduces lipolysis also induces counter-regulatory processes manifested as tolerance development and rebound (Ahlström et al., 2011, Blackard and Heidingsfelder, 1969, Dobbins et al., 2015, Oh et al., 2011, Pereira, 1967, Worm et al., 1994). Thus, development of therapeutic agents that maintain the anti-lipolytic effect of GPR109A activation, but are not associated with the undesired effects of GPR109A, could significantly improve the treatment of T2DM. Similar to GPR109A, activation of G-protein-coupled receptor 81 (GPR81, also called HCAR1 (hydroxycarboxylic acid receptor 1)) by lactate suppresses lipolysis (Fig. 1), suggesting GPR81 to be a potential drug target for treating T2DM (Boyd et al., 1974, Cai et al., 2008, Gold et al., 1963, Houghton et al., 1971, Liu et al., 2009). GPR81 is primarily expressed in adipose tissue with no evidence of expression in epidermal Langerhans cells (Ge et al., 2008, Wise et al., 2003), indicating that a GPR81 agonist would not confer the flush associated with GPR109A. Indeed, selective GPR81 agonists indicating separation between lipolysis suppression and flush have recently been reported (Sakurai et al., 2014). GPR81 is 52% identical to GPR109A at the amino-acid level and belongs to the same subfamily of receptors as GPR109A and GPR109B (Ahmed et al., 2009, Blad et al., 2011). The high degree of receptor sequence identity suggests that compounds may have dual activity, and GPR109A agonism needs to be monitored during development.Partial agonism of GPR109A has been shown to be a way to avoid flush (Lai et al., 2008), but anti-lipolytic effects still seem to be transient. An in vitro-in vivo correlation (IVIVC) between receptor potency and in vivo effect is fundamental to efficiently design new compounds in a chemical series by in vitro screening (Yamaguchi et al., 2013, Yu et al., 2006). A sufficiently good IVIVC confers reductions in cost and number of in vivo experiments. When dealing with multiple-target in vivo pharmacology where the targets are studied one at a time in vitro, the relationship between in vitro and in vivo effects may become difficult to discern. To some degree, this may be overcome by complex in vitro or ex vivo methods that increase confidence in the in vivo effect of the compounds before proceeding to in vivo experiments, but at the expense of being more resource-intensive.