Wang Tongtong, Cui Xueqin, Xie Ling, Xing Roumei, You Panpan, Zhao Yongliang, Yang Yiqing, Xu Yongqian, Zeng Li, Chen Huaqing, Liu Mingyao
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Bioray Laboratories Incorporation, Shanghai, China.
Front Physiol. 2018 Mar 13;9:209. doi: 10.3389/fphys.2018.00209. eCollection 2018.
GPR54, Kisspeptin-1 receptor (KISS1R), a member of rhodopsin family, plays a critical role in puberty development and has been proposed to be involved in regulation of energy metabolism. This study aims to explore the function of GPR54 in adipogenesis, lipid metabolism, and obesity in addition to its effect through hormones. Results showed that when fed a high-fat diet, the weight growth of castrated or ovariectomized mice was significantly slower than that of WT control, together with a lower triglyceride concentration. The ratio of white adipose tissue was lower, and average size of adipocytes was smaller in mice. Meanwhile, there were less adipose tissue macrophages (ATMs), especially pro-inflammatory macrophages. Expression of inflammatory related genes also indicated that inflammatory response caused by obesity was not as drastic in mice as in WT mice. Liver triglyceride in mice was reduced, especially in female mice. On the other hand, oil drop formation was accelerated when hepatocytes were stimulated by kisspeptin-10 (Kp-10). Primary mesenchymal stem cells (MSCs) of mice were less likely to differentiate into adipocytes. When stimulated by Kp-10, 3T3-L1 cell differentiation into adipocytes was accelerated and triglyceride synthesis was significantly promoted. These data indicated that GPR54 could affect obesity development by promoting adipocyte differentiation and triglyceride accumulation. To further elucidate the mechanism, genes related to lipid metabolism were analyzed. The expression of genes involved in lipid synthesis including PPARγ, ACC1, ADIPO, and FAS was significantly changed in mice. Among them PPARγ which also participate in adipocyte differentiation displayed a marked reduction. Moreover, phosphorylation of ERK, which involved in GPR54 signaling, was significantly decreased in mice, suggesting that GPR54 may promote lipid synthesis and obesity development by activating MAP kinase pathway. Therefore, in addition to the involvement in hormone regulation, our study demonstrated that GPR54 directly participates in obesity development by promoting adipocyte differentiation and fat accumulation. This provided evidence of involvement of GPR54 in lipid metabolism, and revealed new potentials for the identification and development of novel drug targets for metabolic diseases.
GPR54，即亲吻素-1受体（KISS1R），属于视紫红质家族成员，在青春期发育中起关键作用，并且有人提出它参与能量代谢的调节。本研究旨在探究GPR54在脂肪生成、脂质代谢和肥胖中的作用，以及其通过激素产生的影响。结果显示，在高脂饮食喂养时，去势或卵巢切除小鼠的体重增长明显慢于野生型对照小鼠，同时甘油三酯浓度较低。小鼠的白色脂肪组织比例较低，脂肪细胞平均大小较小。与此同时，脂肪组织巨噬细胞（ATM）较少，尤其是促炎性巨噬细胞。炎症相关基因的表达也表明，肥胖引起的炎症反应在小鼠中不如在野生型小鼠中剧烈。小鼠肝脏甘油三酯减少，尤其是雌性小鼠。另一方面，当肝细胞受到亲吻素-10（Kp-10）刺激时，油滴形成加速。小鼠的原代间充质干细胞（MSC）分化为脂肪细胞的可能性较小。当受到Kp-10刺激时，3T3-L1细胞向脂肪细胞的分化加速，甘油三酯合成显著促进。这些数据表明，GPR54可通过促进脂肪细胞分化和甘油三酯积累来影响肥胖的发展。为进一步阐明机制，对脂质代谢相关基因进行了分析。参与脂质合成的基因，包括PPARγ、ACC1、ADIPO和FAS的表达在小鼠中发生了显著变化。其中也参与脂肪细胞分化的PPARγ表现出明显降低。此外，参与GPR54信号传导的ERK磷酸化在小鼠中显著降低，表明GPR54可能通过激活丝裂原活化蛋白激酶途径促进脂质合成和肥胖发展。因此，除了参与激素调节外，我们的研究表明GPR54通过促进脂肪细胞分化和脂肪积累直接参与肥胖发展。这为GPR54参与脂质代谢提供了证据，并揭示了代谢疾病新型药物靶点识别和开发的新潜力。
