D-Allulose Regulates Obesity via Endoplasmic Reticulum Stress-Mediated Glucagon-Like Peptide-1 Receptor Pathway

Aims: Obesity remains a major global health issue, with the increasing focus on the incretin hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) for therapeutic strategies. D-allulose is predicted to modulate GLP-1R via mechanisms linked to endoplasmic reticulum stress and reactive oxygen species (ROS) pathways, positively influencing GLP-1R stability and functionality. This study investigates the potential of D-allulose as a therapeutic and preventive agent against obesity. It focuses on the impact of D-allulose on adipocyte differentiation and obesity in high-fat diet (HFD)-administered and GLP-1R knockout (KO) mice over 12 weeks. Results: D-allulose effectively regulated adipocyte differentiation by inhibiting the NADP+/NADPH-ROS-inositol-requiring enzyme 1α (IRE1α)-regulated IRE1-dependent decay (RIDD) axis, resulting in controlled decay of GLP-1R, a newly identified RIDD target. Furthermore, in vivo studies revealed that D-allulose administration significantly regulated body weight and other obesity parameters in HFD-fed mice. However, these effects were not observed in GLP-1R KO mice, suggesting that the antiobesity effects of D-allulose rely on the presence of GLP-1R. Innovation and Conclusion: This study highlights the efficacy of D-allulose in controlling obesity through mechanisms dependent on GLP-1R, suggesting its potential as an effective treatment for obesity with normal GLP-1R function. Antioxid. Redox Signal. 43, 819–832.