Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate.
The genetic determinants of interindividual differences in energy expenditure (EE) are not well established. Sphingolipids have been proposed to influence EE by altering mitochondrial function.
Association analysis of genetic variants in genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in CERS2 associated with higher sleeping EE assessed by whole-room indirect calorimetry.
The rs267738 variant was associated with increased glucose production under basal and insulin-stimulated conditions and with decreased basal mitochondrial respiration.
The rs267738 missense variant may affect the expression of key gluconeogenic genes G6PC1 and PCK1.
Clinical trials reg. no. NCT00340132, clinicaltrials.gov
This article contains supplementary material online at https://doi.org/10.2337/figshare.25864279.
