Reducing ether lipids improves Drosophila overnutrition-associated pathophysiology phenotypes via a switch from lipid...

High-calorie diets increase the risk of developing obesity, cardiovascular disease, type-two diabetes (T2D), and other comorbidities. These "overnutrition" diets also promote the accumulation of a variety of harmful lipids in the heart and other peripheral organs, known as lipotoxicity. However, the mechanisms underlying lipotoxicity and its influence on pathophysiology remain unknown. Our study uses genetics to identify the role of ether lipids, a class of potential lipotoxins, in a Drosophila model of overnutrition. A high-sugar diet (HSD) increases ether lipids and produces T2D-like pathophysiology phenotypes, including obesity, insulin resistance, and cardiac failure. Therefore, we targeted ether lipid biosynthesis through the enzyme dihydroxyacetonephosphate acyltransferase (encoded by the gene DHAPAT). We found that reducing DHAPAT in the fat body improved TAG and glucose homeostasis, cardiac function, respiration, and insulin signaling in flies fed a HSD. The reduction of DHAPAT may cause a switch in molecular signaling from lipogenesis to fatty acid oxidation via activation of a PPARα-like receptor, as bezafibrate produced similar improvements in HS-fed flies. Taken together, our findings suggest that ether lipids may be lipotoxins that reduce fitness during overnutrition.