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Updated: Aug 1, 2025
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under
Liam D Hurley1, Hugo Lee1, Gina Wade2
1Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Abstract:
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 Ormdl3 within pancreatic β-cells (Ormdl3 β-/-). We show that loss of β-cell Ormdl3 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 Ormdl3 β-/- 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 Ormdl3 alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, however, β-cell-specific loss of Ormdl3 does significantly alter levels of specific sphingolipid species in islets upon high fat feeding.
Insights
Loss of Ormdl3 in pancreatic beta cells does not affect glucose homeostasis. However, high-fat diet challenges reveal altered sphingolipid levels in these cells, indicating a role in diet-induced metabolic changes.
Area of Science:
- Endocrinology and Metabolism
- Cell Biology
- Lipid Metabolism
Background:
- Chronic sphingolipid elevation is linked to pancreatic beta-cell failure.
- ORMDL3 is a key regulator of sphingolipid homeostasis.
- The specific role of ORMDL3 in pancreatic beta-cell pathophysiology is not well understood.
Purpose of the Study:
- To investigate the function of ORMDL3 in pancreatic beta-cell pathophysiology.
- To determine the impact of beta-cell-specific Ormdl3 deletion on glucose homeostasis and insulin sensitivity.
- To analyze sphingolipid profiles in islets lacking Ormdl3 under metabolic stress.
Main Methods:
- Generation of a mouse model with beta-cell-specific Ormdl3 deletion (Ormdl3^β-/-).
- Assessment of glucose tolerance, insulin sensitivity, and insulin secretion.
- Analysis of islet morphology and cellular ceramide levels.
- Lipidomics analysis of islets following high-fat diet challenge.
Main Results:
- Loss of beta-cell Ormdl3 did not affect glucose tolerance, insulin sensitivity, insulin secretion, or islet morphology on a standard diet.
- High-fat diet challenge in Ormdl3^β-/- mice showed no alterations in metabolic parameters or islet architecture.
- Lipidomics revealed significantly higher levels of very long chain ceramides in the islets of Ormdl3^β-/- mice on a high-fat diet.
Conclusions:
- Beta-cell-specific loss of Ormdl3 alone is insufficient to impair beta-cell function or whole-body glucose/insulin homeostasis.
- Beta-cell-specific Ormdl3 deficiency significantly alters specific sphingolipid species levels in islets under high-fat feeding conditions.
- These findings suggest a role for ORMDL3 in regulating islet sphingolipid composition during metabolic stress.
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