Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Life Sci. 2021 Aug 15;279:119677. doi: 10.1016/j.lfs.2021.119677. Epub 2021 May 31.
Pancreastatin (PST) is a crucial bioactive peptide derived from chromogranin A (CHGA) proprotein that exhibits an anti-insulin effect on adipocytes. Herein, we investigated the effects of PST on brown adipose tissues (BAT) and white adipose tissue (WAT) in connection with uncoupling protein-1 (UCP-1) regulated energy expenditure in high fructose diet (HFrD) fed and vinylcyclohexenediepoxide (VCD) induced perimenopausal rats.
We administered VCD in rats for 17 consecutive days and fed HFrd for 12 weeks. After 12 weeks estradiol and progesterone levels were detected. Furthermore, detection of glucose tolerance, insulin sensitivity, and body composition revealed impaired glucose homeostasis and enhanced PST levels. Effects of enhanced PST on UCP-1 level in BAT and WAT of perimenopausal rats were further investigated.
Reduced serum estradiol, progesterone, and attenuated insulin response confirmed perimenopausal model development. Furthermore, enhanced PST serum level and its increased expression in BAT and WAT downregulated the UCP-1 expression. Subsequently, impaired ATP level, NADP/NADPH ratio, citrate synthase activity, enhanced mitochondrial reactive oxygen species (ROS) generation and perturbed mitochondrial membrane potential, further exacerbated mitochondrial dysfunction, cellular ROS production, and promoted apoptosis. Interestingly, PST inhibition by PST inhibitor peptide-8 (PSTi8) displayed a favorable impact on UCP-1 and energy expenditure.
The aforementioned outcomes indicated the substantial role of PST in altering the UCP-1 expression and associated energy homeostasis. Hence our results corroborate novel avenues to unravel the quest deciphering PST's role in energy homeostasis and its association with perimenopause.
胰增血糖素原（PST）是一种源自嗜铬粒蛋白 A（CHGA）前体蛋白的重要生物活性肽，对脂肪细胞具有抗胰岛素作用。在此，我们研究了 PST 在高脂肪饮食（HFrD）喂养和乙烯环已二烯二氧化物（VCD）诱导的围绝经期大鼠中与解偶联蛋白-1（UCP-1）调节能量消耗相关的棕色脂肪组织（BAT）和白色脂肪组织（WAT）中的作用。
我们连续 17 天给大鼠注射 VCD，并喂养 HFrD 12 周。12 周后检测雌二醇和孕酮水平。此外，葡萄糖耐量、胰岛素敏感性和身体成分检测显示葡萄糖稳态受损和 PST 水平升高。进一步研究了 PST 对围绝经期大鼠 BAT 和 WAT 中 UCP-1 水平的影响。
血清雌二醇、孕酮降低，胰岛素反应减弱，证实了围绝经期模型的建立。此外，PST 血清水平升高及其在 BAT 和 WAT 中的表达增加，下调了 UCP-1 的表达。随后，ATP 水平降低，NADP/NADPH 比值、柠檬酸合酶活性降低，线粒体活性氧（ROS）生成增加，线粒体膜电位紊乱，进一步加剧了线粒体功能障碍、细胞 ROS 产生和促进细胞凋亡。有趣的是，PST 抑制剂肽-8（PSTi8）抑制 PST 显示出对 UCP-1 和能量消耗的有利影响。
上述结果表明 PST 在改变 UCP-1 表达和相关能量稳态方面具有重要作用。因此，我们的结果为揭示 PST 在能量稳态及其与围绝经期的关系中的作用提供了新的途径。
