Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

Hugo Lee; Rachel J Fenske; Tugce Akcan; Elliot Domask; Dawn B Davis; Michelle E Kimple; Feyza Engin

doi:10.1016/j.isci.2020.101324

Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

iScience. 2020 Jul 24;23(7):101324. doi: 10.1016/j.isci.2020.101324. Epub 2020 Jun 29.

Authors

Hugo Lee¹, Rachel J Fenske², Tugce Akcan¹, Elliot Domask¹, Dawn B Davis³, Michelle E Kimple⁴, Feyza Engin⁵

Affiliations

¹ Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53706, USA.
² Interdepartmental Graduate Program in Nutritional Sciences, Madison, WI 53706, USA; Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
³ Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
⁴ Interdepartmental Graduate Program in Nutritional Sciences, Madison, WI 53706, USA; Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Cell and Regenerative Biology, Madison, WI 53705, USA; Department of Academic Affairs, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53706, USA; Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53705, USA. Electronic address: fengin@wisc.edu.

Abstract

The orosomucoid-like (Ormdl) proteins play a critical role in sphingolipid homeostasis, inflammation, and ER stress, all of which are associated with obesity and βcell dysfunction. However, their roles in β cells and obesity remain unknown. Here, we show that islets from overweight/obese human donors displayed marginally reduced ORMDL1-2 expression, whereas ORMDL3 expression was significantly downregulated compared with islets from lean donors. In contrast, Ormdl3 was substantially upregulated in the islets of leptin-deficient obese (ob/ob) mice compared with lean mice. Treatment of ob/ob mice and their islets with leptin markedly reduced islet Ormld3 expression. Ormdl3 knockdown in a β cell line induced expression of pro-apoptotic markers, which was rescued by ceramide synthase inhibitor fumonisin B1. Our results reveal differential expression of Ormdl3 in the islets of a mouse model and humans with obesity, highlight the potential effect of leptin in this differential regulation, and suggest a role for Ormdl3 in β cell apoptosis.

Keywords: Biological Sciences; Endocrinology.

Abstract

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