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
Affiliations
Hugo Lee
Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53706, USA
Rachel J. Fenske
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
Tugce Akcan
Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53706, USA
Elliot Domask
Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, WI 53706, USA
Dawn B. Davis
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
Michelle E. Kimple
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
Feyza Engin
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; Corresponding author
Summary: 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.
