Oxyntomodulin

Oxyntomodulin is a 37-amino-acid peptide hormone that simultaneously activates both the glucagon-like peptide-1 receptor and the glucagon receptor, thereby regulating appetite, energy expenditure, and blood glucose levels^[1]. Oxyntomodulin is a product of the glucagon precursor proglucagon and is produced and released by intestinal L-cells after processing by prohormone convertase ^[2]. Oxyntomodulin holds potential for the treatment of diabetes and obesity^[3-4].

In vitro, pretreatment of SH-SY5Y cells with Oxyntomodulin (10–1000nM) for 1 hour, followed by stimulation with glutamate (100–150μM) or hydrogen peroxide (150μM) for 24 hours, significantly increased cell viability and reduced cell death induced by glutamate excitotoxicity and oxidative stress^[5].

In vivo, Oxyntomodulin (4–25μg per mouse) was administered intravenously or intraperitoneally to 8–24-week-old C57BL/6J mice to simulate the regulation of liver circadian rhythms by food intake. When administered early in the circadian cycle, Oxyntomodulin acutely induced the expression of core liver clock genes Per1/2 and reset the rhythmic expression of hepatic clock genes (Per2, Dbp) and metabolism-related genes (Foxo1, Pdk4, Slc2a2), resulting in phase delays or reduced amplitude^[6]. In Wistar rats weighing 180–400g, intraperitoneal injection of Oxyntomodulin (3–100nmol/kg) dose-dependently inhibited fasting-induced refeeding and dark-phase feeding without delaying gastric emptying. Additionally, peripheral injection of Oxyntomodulin significantly reduced fasting plasma ghrelin levels and increased c-fos immunoreactivity in the hypothalamic arcuate nucleus (ARC), suggesting that it suppresses appetite by activating ARC neurons^[7].

References:
[1] Holst JJ, Rosenkilde MM. Oxyntomodulin - past, present and future. Peptides. 2025 Jun;188:171393.
[2] Holst JJ, Albrechtsen NJW, Gabe MBN, et al. Oxyntomodulin: Actions and role in diabetes. Peptides. 2018 Feb;100:48-53.
[3] Zhihong Y, Chen W, Qianqian Z, et al. Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity. Peptides. 2023 Apr;162:170955.
[4] Wynne K, Field BC, Bloom SR. The mechanism of action for oxyntomodulin in the regulation of obesity. Curr Opin Investig Drugs. 2010 Oct;11(10):1151-7.
[5] Li Y, Wu KJ, Yu SJ, et al. Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke. Exp Neurol. 2017 Feb;288:104-113.
[6] Landgraf D, Tsang AH, Leliavski A, et al. Oxyntomodulin regulates resetting of the liver circadian clock by food. Elife. 2015 Mar 30;4:e06253.
[7] Dakin CL, Small CJ, Batterham RL, et al. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology. 2004 Jun;145(6):2687-95.

Oxyntomodulin是一种由37个氨基酸组成的肽类激素，能够同时激活胰高血糖素样肽-1受体和胰高血糖素受体，从而调节食欲、能量消耗和血糖水平^[1]。Oxyntomodulin是胰高血糖素前体胰高血糖素原的产物，经过前体激素原转化酶加工后，由肠道内分泌L细胞产生和释放^[2]。Oxyntomodulin具有治疗糖尿病和肥胖的潜力^[3-4]。

在体外，Oxyntomodulin（10–1000nM）预处理SH-SY5Y细胞1h，随后以谷氨酸（100–150μM）或过氧化氢（150μM）刺激24h，显著增加细胞活力，并降低谷氨酸兴奋性毒性和氧化应激诱导的细胞死亡^[5]。

在体内，Oxyntomodulin（4–25μg/只）通过静脉或腹腔注射处理8–24周龄C57BL/6J小鼠，用于模拟食物摄入对肝脏昼夜节律的调控。Oxyntomodulin在昼夜周期早期给药可诱导肝脏核心时钟基因Per1/2的急性表达，并重置肝时钟基因（Per2、Dbp）及代谢相关基因（Foxo1、Pdk4、Slc2a2）的节律性表达，导致相位延迟或振幅减弱^[6]。Oxyntomodulin（3–100nmol/kg）通过腹腔注射处理180–400g的Wistar大鼠。Oxyntomodulin剂量依赖性地抑制禁食诱导的再摄食和暗期摄食，且不延迟胃排空。此外，外周注射Oxyntomodulin显著降低空腹血浆ghrelin水平，并诱导下丘脑弓状核（ARC）中c-fos免疫反应性增加，提示其通过激活ARC神经元抑制食欲^[7]。