Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8577, Japan.
Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 112-8610, Japan.
Nutrients. 2023 Dec 21;16(1):38. doi: 10.3390/nu16010038.
We previously reported that piceatannol (PIC) had an anti-obesity effect only in ovariectomized (OVX) postmenopausal obesity mice. PIC was found to induce the phosphorylation of hormone-sensitive lipase (pHSL) in OVX mice. To elucidate the mechanism by which PIC activates HSL, we investigated the effect of PIC using 3T3-L1 adipocytes. PIC induced HSL phosphorylation at Ser563 in 3T3-L1 cells, as in vivo experiments showed. pHSL (Ser563) is believed to be activated through the β-adrenergic receptor (β-AR) and protein kinase A (PKA) pathways; however, the addition of a selective inhibitor of β-AR did not inhibit the effect of PIC. The addition of a PKA inhibitor with PIC blocked pHSL (Ser563), suggesting that the effects are mediated by PKA in a different pathway than β-AR. The addition of G15, a selective inhibitor of the G protein-coupled estrogen receptor (GPER), reduced the activation of HSL by PIC. Furthermore, PIC inhibited insulin signaling and did not induce pHSL (Ser565), which represents its inactive form. These results suggest that PIC acts as a phytoestrogen and phosphorylates HSL through a novel pathway that activates GPER and its downstream PKA, which may be one of the inhibitory actions of PIC on fat accumulation in estrogen deficiency.
我们之前报道过白藜芦醇（PIC）仅对去卵巢（OVX）绝经后肥胖小鼠具有抗肥胖作用。研究发现，PIC 可诱导 OVX 小鼠中激素敏感脂肪酶（HSL）的磷酸化。为了阐明 PIC 激活 HSL 的机制，我们使用 3T3-L1 脂肪细胞研究了 PIC 的作用。PIC 诱导 3T3-L1 细胞中 HSL 在 Ser563 位点的磷酸化，正如体内实验所示。pHSL（Ser563）被认为通过β-肾上腺素能受体（β-AR）和蛋白激酶 A（PKA）途径激活；然而，添加β-AR 的选择性抑制剂并不能抑制 PIC 的作用。与 PIC 一起添加 PKA 抑制剂可阻断 pHSL（Ser563），表明这些作用是通过 PKA 在与β-AR 不同的途径介导的。添加 G 蛋白偶联雌激素受体（GPER）的选择性抑制剂 G15 可减少 PIC 对 HSL 的激活。此外，PIC 抑制胰岛素信号转导，并且不会诱导 pHSL（Ser565），这代表其无活性形式。这些结果表明，PIC 作为植物雌激素，通过激活 GPER 及其下游 PKA 的新途径磷酸化 HSL，这可能是 PIC 抑制雌激素缺乏引起的脂肪积累的一种抑制作用。
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