Schwartzkopf Chad D, Hadcock John R, Liu Guang, Germano Peter, Roux Julien, Shea Courtney M, Buys Emmanuel S, Jones Juli E
Cyclerion Therapeutics, Cambridge, MA, United States.
Biomeostasis, Marseille, France.
Front Pharmacol. 2022 Mar 4;13:852080. doi: 10.3389/fphar.2022.852080. eCollection 2022.
Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed on 60% high-fat diet (HFD, DIO mice). At 14 weeks old, the DIO mice were either maintained on HFD or switched to HFD with praliciguat (6-mg/kg). Day 28 samples were collected for biomarker analysis. In a second study under the same paradigm, indirect calorimetry was performed on days 8, 9, 20, 21, 32, and 33 and an oral lipid tolerance test (LTT) on day 38. Mice treated 28 days with praliciguat had lower levels of fasting plasma insulin, C-peptide, triglycerides, and HOMA-IR (homeostatic model assessment for insulin resistance) than DIO controls. In addition, energy expenditure was higher in praliciguat-treated than in DIO control mice on days 9, 20, 32, and 33; and day-38 triglycerides were lower. HFD-induced increases in gene expression of liver TNF-ɑ, lipoprotein lipase (), and patatin-like phospholipase domain-containing protein 3 () in control DIO mice were attenuated in praliciguat-treated DIO mice. The positive metabolic effects observed in praliciguat-treated mice were associated with the restoration of liver PI3K (pAKT-Thr308) signaling, but not MAPK (pERK). In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with praliciguat treatment in DIO mice.
普拉西胍是一种可溶性鸟苷酸环化酶刺激剂，在代谢功能障碍的临床前模型中可引发血流动力学、抗炎和抗纤维化作用。我们在处于热中性环境的小鼠饮食诱导肥胖（DIO）模型中评估了普拉西胍的代谢作用。6周龄时，雄性C57BL/6N小鼠要么维持低脂饮食（LFD，瘦小鼠），要么置于60%高脂饮食（HFD，DIO小鼠）。14周龄时，DIO小鼠要么维持HFD饮食，要么改用含普拉西胍（6毫克/千克）的HFD饮食。收集第28天的样本进行生物标志物分析。在同一实验范式下的第二项研究中，于第8、9、20、21、32和33天进行间接量热法测定，并于第38天进行口服脂质耐量试验（LTT）。用普拉西胍治疗28天的小鼠，其空腹血浆胰岛素、C肽、甘油三酯水平及HOMA-IR（胰岛素抵抗稳态模型评估）均低于DIO对照组。此外，在第9、20、32和33天，用普拉西胍治疗的小鼠的能量消耗高于DIO对照小鼠；且第38天的甘油三酯水平更低。在对照DIO小鼠中，HFD诱导的肝脏TNF-α、脂蛋白脂肪酶（）和含patatin样磷脂酶结构域蛋白3（）基因表达增加在普拉西胍治疗的DIO小鼠中减弱。在普拉西胍治疗的小鼠中观察到的积极代谢作用与肝脏PI3K（pAKT-Thr308）信号通路的恢复有关，而非与MAPK（pERK）信号通路有关。总之，用普拉西胍治疗的DIO小鼠能量利用增加、胰岛素敏感性改善且血浆甘油三酯水平降低。这些结果说明了普拉西胍治疗DIO小鼠所产生的代谢作用。
