AUTHOR=Hurley Liam D. , Lee Hugo , Wade Gina , Simcox Judith , Engin Feyza 

TITLE=Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under obesogenic conditions

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1170461

DOI=10.3389/fendo.2023.1170461

ISSN=1664-2392

ABSTRACT=<p>Chronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lacking <italic>Ormdl3</italic> within pancreatic β-cells (<italic>Ormdl3</italic><sup>β-/-</sup>). We show that loss of β-cell <italic>Ormdl3</italic> does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while <italic>Ormdl3</italic><sup>β-/-</sup> mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of <italic>Ormdl3</italic> alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, however, β-cell-specific loss of <italic>Ormdl3</italic> does significantly alter levels of specific sphingolipid species in islets upon high fat feeding.</p>