Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Abstract

Diet-induced obesity (DIO) leads to dysfunctional feeding behavior. But the precise molecular nodes that are dysregulated by DIO that alter satiety sensing and feeding motivation are not fully disentangled. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime, in Drosophila, we sought to address how lipid alteration in fat cells alters feeding motivation. We find that long-term exposure to an HSD increases baseline feeding in flies. However, prolonged exposure to HSD degrades the hunger-driven feeding (HDF) response. Lipidomics analysis reveals that longitudinal exposure to HSD significantly alters whole body phospholipid profiles. Then, performing a systematic screen for phospholipid enzymes, we identify that a specific enzyme PECT, a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2, was critical to maintaining hunger-driven feeding motivation. We show that disrupting PECT only in the fat body causes insulin-resistant phenotypes and a loss of hunger-driven feeding. Excitingly, we find that overexpression of PECT restores HSD-induced loss of hunger-driven feeding response. Strikingly human studies have noted a correlation between PCYT2/PECT levels and clinical obesity. Now, our unbiased studies in Drosophila provide specific genetic evidence for PECT in maintaining nutrient sensing during DIO. Our study provides novel insights on the role of phospholipids in interorgan communication of nutrient status.