Guanylin-Guanylyl cyclase-C signaling in macrophages regulates mesenteric fat inflammation induced by high-fat diet
Guanylin-Guanylyl cyclase-C signaling in macrophages regulates mesenteric fat inflammation induced by high-fat diet
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DOI：
10.1507/endocrj.ej15-0193
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发表时间：
2015-10-20
影响因子：
2
通讯作者：
Date, Yukari
中科院分区：
文献类型：
--
作者：
Hasegawa, Kazuya;Akieda-Asai, Sayaka;Date, Yukari
鸟苷酸 (Gn) 是一种生物活性肽，其受体鸟苷酸环化酶-C (GC-C) 主要存在于肠道中，维持体液的稳态。最近，发现巨噬细胞过度表达 Gn 和 GC-C 的大鼠对饮食引起的肥胖具有抵抗力。考虑到肥胖与白色脂肪组织的慢性炎症状态密切相关，Gn GC-C 巨噬细胞可能有助于炎症的调节。在本研究中，我们通过评估 Gn GC-C 的第二信使环 GMP (cGMP)、cGMP 依赖性蛋白激酶 (PKG) 和 PKG 的靶蛋白磷酸化血管舒张刺激磷蛋白 (VASP) 的水平，研究了 Gn 和 GC-C 转基因大鼠（双转基因 [dTg] 大鼠）肠系膜脂肪的炎症状态。 dTg 大鼠的 cGMP 水平高于喂养相同饮食的 WT 大鼠。虽然喂食标准饮食（STD）的 WT 和 dTg 大鼠之间的 PKG 和磷酸化 VASP 水平没有显着差异，但喂食高脂肪饮食（HFD）的 dTg 大鼠中的这些水平与 HFD WT 大鼠的水平相比显着升高。此外，HFD dTg 大鼠肠系膜脂肪中促炎因子的 mRNA 水平低于 HFD WT 大鼠，且与 STD WT 和 dTg 大鼠的水平相似。这些结果表明巨噬细胞中的 Gn GC-C 系统调节 cGMP PKG VASP 通路并通过下调促炎因子来控制肥胖。
Guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), are primarily present in the intestine and maintain homeostasis in body fluids. Recently, rats whose macrophages overexpress Gn and GC-C were found to be resistant to diet-induced obesity. Considering that obesity is strongly related to a chronic inflammatory state in white adipose tissues, it is possible that Gn GC-C macrophages contribute to the regulation of inflammation. In the present study, we investigated the inflammatory state of mesenteric fat in rats transgenic for both Gn and GC-C (double-transgenic [dTg] rats) by evaluating the levels of cyclic GMP (cGMP), a second messenger of Gn GC-C, cGMP-dependent protein kinase (PKG), and phosphorylated vasodilator-stimulated phosphoprotein (VASP), a target protein of PKG. The levels of cGMP in dTg rats was higher than in WT rats fed the same diet. Although there were no significant differences in levels of PKG and phosphorylated VASP between WT and dTg rats fed a standard diet (STD), these levels in dTg rats fed a high fat diet (HFD) were markedly increased compared with levels in HFD WT rats. Furthermore, mRNA levels of proinflammatory factors in mesenteric fat were lower in HFD dTg rats than in HFD WT rats and were similar to levels in STD WT and dTg rats. These results indicate that the Gn GC-C system in macrophages regulates the cGMP PKG VASP pathway and controls obesity through the downregulation of proinflammatory factors.