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

  • Antioxid Redox Signal. 2025 Dec;43(16-18):819-832. doi: 10.1177/15230864251399183.
Geum-Hwa Lee  1 ,  Hwa-Young Lee  1  2 ,  Young Jae Lim  2 ,  Ji-Hyun Kim  2 ,  So-Young Rah  3 ,  Myung Ja Chung  4 ,  Se Young Park  5 ,  Soonok Sa  5 ,  Hyewon Lee  6 ,  Yunjo Soh  6 ,  Junghyun Kim  7 ,  Han-Jung Chae  1  2  6  8
Affiliations
  • 1. Research Institute of Clinical Medicine of Jeonbuk, National University-Biomedical Research Institute of Jeonbuk, National University Hospital, Jeonju, Republic of Korea.
  • 2. Non-Clinical Evaluation Center Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, Republic of Korea.
  • 3. Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.
  • 4. Department of Pathology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.
  • 5. Food Biotech R&D Center, Samyang Corp., Seongnam-si, Republic of Korea.
  • 6. School of Pharmacy, Jeonbuk National University, Jeonju, Republic of Korea.
  • 7. Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea.
  • 8. Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea.
PMID: 41327798 DOI: 10.1177/15230864251399183
Abstract

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.

Keywords
D-allulose; GLP-1 receptor; glucagon-like peptide-1; obesity; regulated IRE1-dependent decay.
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