Transcriptional regulation of multi-tissue mRNA expression by L-arabinose mitigates metabolic disorders in leptin receptor-deficient mice

L-arabinose, a sugar substitute, exhibits anti-diabetic effects due to its lower caloric content than conventional sugar. However, the comprehensive molecular mechanisms underlying its organ-to-organ interactions remain elusive in transgenic mouse models. Therefore, we investigated these anti-diabetic effects using mRNA sequencing analysis across multiple tissues. We used leptin receptor-deficient mice subjected to a normal diet with sucrose (SUC), SUC supplemented with erythritol (ERY), and SUC supplemented with L-arabinose (ARA) for 16 weeks. Prolonged supplementation with L-arabinose significantly lowered fasting blood glucose and HOMA-IR levels, improved glucose tolerance, and markedly reduced body fat in the leptin receptor-deficient mice without affecting food and energy intake. The ARA group exhibited decreased activities of gluconeogenic enzymes (PEPCK, G6Pase) and increased glycolytic enzyme activity, signifying enhanced insulin sensitivity. Additionally, significant alterations in gene expression related to fatty acid metabolism and insulin resistance were observed, including a notable increase in the transcription of genes essential for fatty acid oxidation. L-arabinose supplementation also led to improved myogenesis and a reduction in chronic inflammation, indicating potential efficacy in mitigating diabetic sarcopenia. Overall, this study positions L-arabinose supplementation as a promising therapeutic strategy for managing insulin resistance and its associated complications, meriting further investigation into its role in diabetes management. •L-arabinose supplementation notably reduced fasting blood glucose levels and enhanced insulin sensitivity in transgenic mice.•Dietary L-arabinose substantially reduced the body fat mass and ameliorated fatty liver induced by insulin resistance.•Prolonged L-arabinose supplementation improved diabetic sarcopenia with increased mRNA expression related to myogenesis.