Pharmacological protection from a sugar-rich diet through inhibition of Ras/MAPK signaling

Summary: Consumption of sugar-rich diets adversely affects health and reduces life expectancy through the excessive production and storage of triacylglycerides (TAGs), leading to metabolic dysfunction. Here, we show that in Drosophila , pharmacological inhibition of Ras/mitogen-activated protein kinase (MAPK) signaling using the highly specific MEK inhibitor, trametinib, mitigates several of the detrimental effects of a high-sugar diet by reducing TAG accumulation, restoring TAG composition, and increasing survival. Notably, Ras/MAPK activity is required for the transcriptional response to elevated sugar intake, including expression of the glucagon-like hormone, Akh . We further demonstrate that adipokinetic hormone (AKH) is essential for the protective effects of trametinib under high-sugar conditions. Together, our findings support Ras/MAPK signaling as an important link between dietary sugar and metabolic dysfunction and show that its pharmacological inhibition can uncouple excess sugar intake from adverse metabolic outcomes.