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  • Prostaglandins PGs are lipid mediators that exhibit

    2019-08-12

    Prostaglandins (PGs) are lipid mediators that exhibit a variety of physiological properties by interacting specific G protein-coupled receptors (GPCRs) [10]. PGD2 is synthesized from PGH2 through two distinct PGD synthases; lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGD synthase (H-PGDS) [11], former is involved in the regulation of adipogenesis [12]. PGD2 binds to two types of GPCRs, namely DP1 receptors (DP1R) and DP2 receptors (DP2R), with the latter also known as a chemoattractant receptor-homologous molecule on Th2 madecassol (CRTH2) [13]. The DP1R is a Gs-coupled receptor, which increases the intracellular cAMP levels, and the DP2R is a Gi-coupled receptor, which decreases the intracellular cAMP levels [10]. Some PGs are involved in the regulation of adipogenesis [14]. PGE2 and PGF2α are involved in the suppression of the early stage of adipogenesis [15]. Prostacyclin activates adipocyte differentiation [16]. PGD2 enhances the progression of adipogenesis [12]. Moreover, PGD2 is dehydrated to form the J-series PGs such as PGJ2, Δ12-PGJ2 and 15-deoxy Δ12,14-PGJ2 (15d-PGJ2) [17], [18]. Δ12-PGJ2 and 15d-PGJ2 act as ligands for the peroxisome proliferator-activated receptor γ (PPARγ), both of which activate adipogenesis [19], [20], [21]. However, the function of the DPR in adipocytes remains unclear. In this study, we found a novel mechanism to regulate the lipolysis in adipocytes. PGD2 repressed the lipolysis by suppressing the cAMP-PKA-dependent phosphorylation of HSL through the DP2R in adipocytes. Thus, the DP2R has possible therapeutic implications in reducing body weight.
    Materials and methods
    Results
    Discussion Several factors are involved in the regulation of lipolysis in adipose tissues. The lipolysis is stimulated by β-adrenergic signaling through the activation of the cAMP-PKA pathway [27]. This signal activates phosphorylation of the enzymes involved in the lipolysis. In contrast, insulin inhibits β-adrenergic signaling and suppresses the lipolysis. In addition, other factors such as cytokines, growth hormones, and PGs are also involved in this regulation. Although the regulation mechanism of lipolysis has been well characterized [26], the roles of PGs in lipolysis are so complicated. PGE2 reduces the lipolysis [28]. Whereas prostacyclin inhibits the PGE2-mediated lipolysis [29]. Our present study demonstrated for the first time that PGD2 activates the accumulation of intracellular lipids through DP2R in adipocytes (Supplemental Fig. S1). PGD2 has a variety of pharmacological activities including the regulation of adipogenesis (obesity). The expression of L-PGDS is enhanced during adipogenesis [12]. PGD2 activates obesity in PGD2-overproducing mice [30]. However, the regulation of adipocyte differentiation by PGD2 has been complicated, because PGD2 as well as its metabolites are involved in the regulation of adipogenesis via distinct pathways [21]. Δ12-PGJ2 and 15d-PGJ2 activate adipogenesis by binding with PPARγ [19], [20], [21]. However, the inhibition of PPARγ activity could not completely suppress the PGD2-mediated enhancement of adipogenesis [21], suggesting that PGD2 enhances adipogenesis through the PPARγ-dependent and -independent mechanisms in adipocytes. In this study, we found that DP2R was expressed in adipocytes (Fig. 1A). A DP2R agonist, 15R elevated the intracellular TG level (Fig. 1B); however, this elevation was not observed in DP2R KO MEFs (Fig. 3A). Three enzymes, namely ATGL, HSL, and MGL are involved in the lipolytic process, which metabolize TG to glycerol and free fatty acids [26]. Among them, HSL is the rate-limiting enzyme in the lipolysis. HSL activity is elevated by the phosphorylation of Ser563 of HSL by cAMP-dependent PKA [31]. Moreover, the forskolin-induced intracellular cAMP enhanced the activity of PKA, the activation of which was cleared by a DP2R agonist (Fig. 4B). The forskolin-elevated phosphorylation of HSL was reduced by the co-treatment with a DP2R agonist (15R; Fig. 4C). Therefore, PGD2 enhanced the lipid accumulation in adipocytes by inhibiting the lipolysis through suppression of the cAMP-PKA-HSL axis via DP2R. This is the first study to determine that PGD2 suppresses the lipolysis through DP2R in adipocytes.