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.