Vulnerability of the gastric mucosa to the ulcerogenic action of indomethacin and energy metabolism in KK.CG-Ay/J, KK.CG-a/J and C57BL/6J mice

Previously, we demonstrated that the sensitivity of the gastric mucosa to ulcerogenic factors depends on the body's overall condition (Filaretova et al., 2020). The aim of this study was to investigate the vulnerability of the gastric mucosa to the ulcerogenic action of indomethacin (IM) and energy metabolism in mice of the inbred strains C57BL/6J (B6), KK.Cg-a/J (KK), and Agouti mice KK.Cg-Ay/J (KK-Ay), heterozygous for the Agouti yellow lethal gene. The subjects were 90–140–day–old male mice from the B6 strain and two substrains of Kasukabe (KK) mice, established by cross-mating black female KK.Cg-a/a and yellow male KK.Cg-Ay/a mice from the Pavlov Institute breeding colony. The founders of these strains were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). To measure oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), and locomotor activity, the open-circuit Promethion Core™ Multiplexed Respirometry System (Model CAB-16R, Sable Systems Europe GmbH, Berlin, Germany) was used. Data were collected over seven days under artificial light (lights on at 08:00 a.m., off at 08:00 p.m.) and a controlled temperature of 24°C. Energy expenditure (EE), as well as carbohydrates and lipid oxidation rates (utilization), were calculated and normalized to body weight. IM (35 mg/kg) or its vehicle was administered on the 7th day following a 24-h fasting. Four hours after the injection, blood glucose levels were measured. The mice were then decapitated, their stomachs were removed to estimate erosion areas, and trunk blood was collected to measure corticosterone levels. Under basal conditions, all strains exhibited normal diurnal dynamics of EE with no significant differences between them. Both B6 and KK mice maintained normal diurnal dynamics of carbohydrate oxidation and lipid oxidation. In contrast, KK-Ay showed a marked decrease in carbohydrate oxidation and an increase in lipid oxidation during the nighttime, disrupting their diurnal dynamics compared to B6 and KK mice. All strains exibited normal diurnal dynamics of locomotion, however, KK-Ay and KK mice were less active at night compared to B6 mice. During the 24-h fasting before IM administration there were no differences in EE or carbohydrate oxidation among the strains. However, lipid oxidation and locomotor activity were lower in KK and KK-Ay mice compared to B6. IM administration increased carbohydrate oxidation in all strains. Simultaneously, IM reduced EE and lipid oxidation in KK-Ay mice, but had no significant effect on these parameters in KK or B6 mice. KK-Ay mice had larger body weights and relative mass of epididymal fat depots than KK mice . Four hours after IM administration, KK and KK-Ay mice exhibited higher blood glucose levels and lower corticosterone levels compared to B6 mice. The mean area of IM-induced gastric erosions was greater in KK-Ay mice than in KK and B6. These findings suggest that alterations in energy metabolism associated with the Agouti yellow lethal gene are accompanied by increased vulnerability of KK-Ay mice to the ulcerogenic action of IM compared to B6 and KK mice. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.