UC San Diego
Sphingolipid Metabolism : : A Novel Link Between Obesity and Cardiomyopathy
- Author(s): Walls, Jr.
- et al.
Accumulation of the sphingolipid ceramide has been associated with obesity in humans and model systems. Here, we use Drosophila genetic manipulations to cause accumulation or depletion of ceramide and other sphingolipid intermediates. Our results show that sphingolipid modulation is sufficient to induce obesity phenotypes by two distinct mechanisms : 1) Ceramide accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell density and function resulting in caloric intake- independent obesity. 2) Sphingosine 1-Phosphate depletion suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity. These data suggest that ceramide and S1P play active roles in the pathogenesis of obesity. Lipotoxic cardiomyopathy is a form of cardiac dysfunction associated with obesity which results from abnormal myocardial lipid accumulation in the heart. Here, we utilize the fruit fly heart to model ceramide-induced lipotoxic cardiomyopathy. Our results show that ceramide accumulation in sphingosine kinase 2 (SK2) mutant flies induced heart chamber dilation, diastolic dysfunction and arrhythmicity : all classic hallmarks of lipotoxic cardiomyopathy. Conversely, ceramide depletion in serine palmitoyl CoA-transferase (lace) mutant induced heart chamber restriction, diastolic dysfunction and arrhythmicity. Ceramide and sphingosine 1- phosphate (S1P) accumulating sphingosine 1-phophate lyase (Sply) mutant fly heart sizes were unchanged, but did exhibit contractile dysfunction. Additionally, our results show that accumulation of various ceramide species via global knockdown of either sphingosine desaturase (ifc) or sphingosine kinase 1(Sk1) is also sufficient to induce classic hallmarks of lipotoxic cardiomyopathy. However, heart specific knockdown of ifc induced a restricted heart phenotype, while heart specific Sk1 knockdown had no effect, since this gene is not expressed in the Drosophila heart. These data show that systemic contributions from globally accumulated ceramide species are sufficient to induce lipotoxic cardiomyopathy. Furthermore, heart- specific ectopic expression of Sk1 in ifc⁴ mutants prevented heart chamber dilation and tachycardia, but not diastolic dysfunction or arrhythmia, while heart-specific ectopic expression of caspase inhibitor dIAP1 in ifc⁴ mutants induced restricted heart chambers, but prevented tachycardia, diastolic dysfunction and arrhythmia. These data suggest that ceramide and S1P play significant roles in regulating heart size, structure and function