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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

High-Fat Diet Provokes Aberrant Erythropoiesis in IRP1-Deleted Mice, Leading to Paradoxical Improvement of Glucose Tolerance

  • Mikyoung You1,2,3,4
  • Soonkyu Chung3,4
4 affiliations
  1. 1Department of Food and Nutrition, Mokpo National University, Muan-Gun, Jeonnam-Gwangju Special Metropolitan City 58554, Republic of Korea
  2. 2Convergence Center for Green Anti-Aging Research, Mokpo National University, Muan-Gun, Jeonnam-Gwangju Special Metropolitan City 58554, Republic of Korea
  3. 3Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583, USA
  4. 4Department of Nutrition, University of Massachusetts, Amherst, MA 01003, USA
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Abstract

Iron regulatory receptor 1 (IRP1) plays a key regulatory role in iron homeostasis, hypoxia sensing, and erythropoiesis. IRP1 deficiency causes polycythemia in early life, which is worsened by a low-iron diet. A high-fat (HF) diet is a prevalent metabolic insult that causes local hypoxia in adipose tissue, but little is known about the role of IRP1-mediated metabolic adjustments in preserving iron balance. In this study, we hypothesized that deletion of IRP1 fails to control HF-diet-induced hypoxia, thereby exacerbating diet-induced obesity and insulin resistance. HF feeding in IRP1-deficient mice induced a dramatic increase in EPO production, aberrant erythropoiesis, and splenomegaly through the reinstatement of the HIF2 α/EPO pathway. The deletion of IRP1 did not alter body weight gain but caused a paradoxical increase in glucose tolerance compared with WT mice. The 2-DOG uptake assay showed higher RBC-associated radioactivity in IRP1-deficient mice. RBC metabolomic analysis further demonstrated that IRP1 deficiency is associated with elevated metabolite levels generated by glycolysis and the pentose phosphate pathway. Collectively, our work demonstrates that IRP1 plays a critical role in preventing abnormal RBC formation under HF diet-mediated hypoxic conditions. Our work also provides an unexpected insight into RBC metabolism as a novel target against insulin resistance.

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Cite

BibTeXRIS
BibTeX
@article{you2026highfat,
  title = {{High-Fat Diet Provokes Aberrant Erythropoiesis in IRP1-Deleted Mice, Leading to Paradoxical Improvement of Glucose Tolerance}},
  author = {Mikyoung You and Soonkyu Chung},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219968},
  url = {https://www.mdpi.com/1422-0067/27/21/9968},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - High-Fat Diet Provokes Aberrant Erythropoiesis in IRP1-Deleted Mice, Leading to Paradoxical Improvement of Glucose Tolerance
AU  - Mikyoung You
AU  - Soonkyu Chung
PY  - 2026
DA  - 2026/11/06
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219968
UR  - https://www.mdpi.com/1422-0067/27/21/9968
AB  - Iron regulatory receptor 1 (IRP1) plays a key regulatory role in iron homeostasis, hypoxia sensing, and erythropoiesis. IRP1 deficiency causes polycythemia in early life, which is worsened by a low-iron diet. A high-fat (HF) diet is a prevalent metabolic insult that causes local hypoxia in adipose tissue, but little is known about the role of IRP1-mediated metabolic adjustments in preserving iron balance. In this study, we hypothesized that deletion of IRP1 fails to control HF-diet-induced hypoxia, thereby exacerbating diet-induced obesity and insulin resistance. HF feeding in IRP1-deficient mice induced a dramatic increase in EPO production, aberrant erythropoiesis, and splenomegaly through the reinstatement of the HIF2 α/EPO pathway. The deletion of IRP1 did not alter body weight gain but caused a paradoxical increase in glucose tolerance compared with WT mice. The 2-DOG uptake assay showed higher RBC-associated radioactivity in IRP1-deficient mice. RBC metabolomic analysis further demonstrated that IRP1 deficiency is associated with elevated metabolite levels generated by glycolysis and the pentose phosphate pathway. Collectively, our work demonstrates that IRP1 plays a critical role in preventing abnormal RBC formation under HF diet-mediated hypoxic conditions. Our work also provides an unexpected insight into RBC metabolism as a novel target against insulin resistance.
SN  - 1422-0067
ER  -