Abstract
Overnutrition, induced by a high-calorie diet, is associated with obesity, type two diabetes, and cardiovascular disease in a myriad of organisms including flies and humans, although the causal relationship remains to be elucidated. There is an indication that high-calorie diets influence metabolic pathways and lead to an influx of lipid concentration, known as lipotoxicity. However, the mechanism of lipotoxicity remains unknown. In recent studies, investigators have proposed the idea of maximum adipose expandability, where they suggest that habitual consumption of glucose can lead to the complete occupation of triglycerides in fat storage, leaving newly synthesized free fatty acids and their derivatives to toxically accumulate in peripheral tissues, such as the heart (Unger et al., 2010, Virtue et al, 2010). Our previous data have supported a Drosophila model where cardiac arrhythmia is linked with overnutrition through lipotoxicity via a reduction in triglycerides, the fat storage fatty acids, and an increase of free fatty acids and their derivatives following high sugar feeding(Tuthill et al. 2020). In our study, a genetic knockdown of ether lipid synthesizing enzyme, DHAPAT, has shown amelioration of cardiac function and comorbidities of type two diabetes. A systemic change in the lipidome is also associated with our knockdown after HS-feeding, implicating ether lipid as lipotoxins. Additionally, peroxisomal proliferation is decreased after the HS-fed genetic knockdown, suggesting a novel role of peroxisomes in the maximum expandability model. The results from this study highlight the role of peroxisomal synthesis of ether lipids in lipotoxicity.