ORMDL in metabolic health and disease

Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated fatty acids are substrates for serine palmitoyltransferase (SPT) the rate-limiting step in de novo sphingolipid biosynthesis. The mammalian orosomucoid-like protein isoforms ORMDL1-3 negatively regulate SPT activity. Here we summarize evidence that dysregulation of sphingolipid metabolism and SPT activity correlates with pathogenesis of obesity. This re-view also discusses the current understanding of the function of SPT and ORMDL in obesity and metabolic dis-ease. Gaps and limitations in current knowledge are highlighted together with the need to further understand how ORMDL3, which has been identified as an obesity-related gene, contributes to the pathogenesis of obesity and development of metabolic disease related to its physiological functions. Finally, we point out the needs to move this young field of research forward.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

This article summarizes the evidence that dysregulation of sphingolipid metabolism and serine palmitoyltransferase (SPT) activity is associated with the pathogenesis of obesity. The functions of SPT and ORMDL in obesity and metabolic disease are also discussed. Gaps and limitations in current knowledge are highlighted, along with the need to further understand the role of ORMDL3 in the development of obesity and metabolic disease. The article concludes by emphasizing the importance of advancing research in this field.