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Ivask M, Volke V, Raasmaja A, et al. High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice. Mol Genet Metab. 2021;134(1):203-211doi: 10.1016/j.ymgme.2021.07.002.
Ivask, M., Volke, V., Raasmaja, A., & Kõks, S. (2021). High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice. Molecular genetics and metabolism, 134(1), 203-211. https://doi.org/10.1016/j.ymgme.2021.07.002
Ivask, Marilin, et al. "High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice." Molecular genetics and metabolism vol. 134,1 (2021): 203-211. doi: https://doi.org/10.1016/j.ymgme.2021.07.002
Ivask M, Volke V, Raasmaja A, Kõks S. High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice. Mol Genet Metab. 2021 Sep-Oct;134(1):203-211. doi: 10.1016/j.ymgme.2021.07.002. Epub 2021 Jul 13. PMID: 34312071.
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Mol Genet Metab. 2021 Sep-Oct;134(1):203-211. doi: 10.1016/j.ymgme.2021.07.002. Epub 2021 Jul 13.

High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice.

Molecular genetics and metabolism

Marilin Ivask, Vallo Volke, Atso Raasmaja, Sulev Kõks

Affiliations

  1. Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  2. Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Endocrinology Unit, Tartu University Hospital, Tartu, Estonia.
  3. Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland. Electronic address: [email protected].
  4. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia; Perron Institute for Neurological and Translational Science, Perth, WA, Australia.

PMID: 34312071 DOI: 10.1016/j.ymgme.2021.07.002

Abstract

Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in the wolframin ER transmembrane glycoprotein (WFS1) gene and characterized by diabetes mellitus, diabetes insipidus, optic atrophy and deafness. In experimental models the homozygous Wfs1 mutant mice have a full penetrance and clearly expressed phenotype, whereas heterozygous mutants have a less-pronounced phenotype between the wild-type and homozygous mutant mice. Heterozygous WFS1 mutations have been shown to be significant risk factors for diabetes and metabolic disorders in humans. In the present study we analyzed the response of heterozygous Wfs1 mice to high fat diet (HFD) by exploring potential outcomes and molecular changes induced by this challenge. The HFD treatment increased the body weight (BW) similarly both in Wfs1 wild-type (WT) and heterozygous (HZ) mice, and therefore HFD also prevented the impaired BW gain found in Wfs1 mutant mice. In Wfs1HZ mutant mice, HFD impaired the normalized insulin secretion and the expression of ER stress genes in isolated pancreatic islets. These results suggest that Wfs1HZ mice have a decreased insulin response and pronounced cellular stress response due to a higher sensitivity to HFD as hypothesized. In Wfs1HZ mice, HFD increased the expression of Ire1α and Chop in pancreas and decreased that of Ire1α and Atf4 in liver. The present study shows that HFD can disturb insulin function with an increased ER stress in Wfs1HZ mice and only one functional Wfs1 gene copy is not sufficient to compensate this challenge. In conclusion, our study indicates that quantitative Wfs1 gene deficiency is sufficient to predispose the carriers of single functional Wfs1 copy to diabetes and metabolic syndrome and makes them susceptible to the environmental challenges such as HFD.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: ER stress; High fat diet; Insulin; Wfs1

Conflict of interest statement

Declaration of Competing Interest No conflicts of interest, financial or otherwise, are declared by the author(s).

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