Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic.
Institute of Physiology AS CR, Prague, Czech Republic.
Nutr Diabetes. 2018 Jan 16;8(1):5. doi: 10.1038/s41387-017-0015-8.
BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters.
SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured.
At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure.
We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
背景/目的：促泌乳素释放肽（PrRP）具有降低食物摄入和改善肥胖的潜力，但外周给药后无效。我们之前的研究表明，我们的新型脂质化类似物 PrRP 增强了其在循环中的稳定性，并使其在周围应用后具有中枢作用。本研究的目的是探讨新型 PrRP 类似物棕榈酰化 11 位（palm-PrRP31）是否可以降低 Koletsky 自发性高血压肥胖大鼠（SHROB）的体重和葡萄糖耐量以及其他代谢参数。
受试者/方法：本研究使用了 SHROB 大鼠（n=16），并使用年龄匹配的高血压瘦 SHR 同窝仔鼠（n=16）作为对照。palm-PrRP31 以 5mg/kg 的剂量每天腹膜内注射一次，共 3 周，用于治疗 SHR 和 SHROB（n=8）。在给药期间监测食物摄入量和体重。在实验结束时进行口服葡萄糖耐量试验；收集血浆和组织样本。之后测量动脉血压。
在实验结束时，用载体处理的 SHROB 大鼠表现出典型的代谢综合征参数，包括肥胖、葡萄糖耐量受损、血脂异常和高血压。外周给予 palm-PrRP31 可逐渐降低 SHR 大鼠的体重，但对 SHROB 大鼠无效，尽管两种大鼠的葡萄糖耐量均显著改善。此外，在 SHROB 大鼠中，palm-PrRP31 改善了 HOMA 指数、胰岛素/胰高血糖素比值，并增加了脂肪中的胰岛素受体底物 1 和 2 表达以及下丘脑的胰岛素信号，而对血压没有影响。
我们证明了我们的新型脂质化 PrRP 类似物能够改善肥胖 SHROB 大鼠的葡萄糖耐量，这表明其对葡萄糖代谢的影响独立于瘦素信号和体重减轻。这些数据表明，该类似物具有成为一种同时具有减肥和降血糖特性的化合物的潜力。
