Drosophila HNF4 Directs a Switch in Lipid Metabolism that Supports the Transition to Adulthood

• Published in: Developmental cell 2019-01, Vol.48 (2), p.200-214.e6
• Main Authors: Storelli, Gilles, Nam, Hyuck-Jin, Simcox, Judith, Villanueva, Claudio J., Thummel, Carl S.
• Format: Article
• Language: English
• Subjects: Animals; desiccation; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Energy Metabolism - physiology; Fatty Acids - metabolism; glucose; hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - metabolism; Homeostasis - physiology; hydrocarbon; Lipid Metabolism - physiology; nuclear receptor; oenocyte; transcription; VLCFA
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.11.030

Animals must adjust their metabolism as they progress through development in order to meet the needs of each stage in the life cycle. Here, we show that the dHNF4 nuclear receptor acts at the onset of Drosophila adulthood to direct an essential switch in lipid metabolism. Lipid stores are consumed shortly after metamorphosis but contribute little to energy metabolism. Rather, dHNF4 directs their conversion to very long chain fatty acids and hydrocarbons, which waterproof the animal to preserve fluid homeostasis. Similarly, HNF4α is required in mouse hepatocytes for the expression of fatty acid elongases that contribute to a waterproof epidermis, suggesting that this pathway is conserved through evolution. This developmental switch in Drosophila lipid metabolism promotes lifespan and desiccation resistance in adults and suppresses hallmarks of diabetes, including elevated glucose levels and intolerance to dietary sugars. These studies establish dHNF4 as a regulator of the adult metabolic state. [Display omitted] •Lipid stores are consumed rapidly after Drosophila transitions into adulthood•Drosophila HNF4 directs fatty acid conversion to VLCFA and hydrophobic hydrocarbons•VLCFA/hydrocarbon synthesis ensures adaptation to dry conditions and dietary sugars•The role for HNF4 in regulating VLCFA synthesis is conserved between flies and mice Storelli et al. show that the Drosophila HNF4 nuclear receptor couples lipid metabolism with development to meet the needs of adult life. Drosophila HNF4 directs the rapid conversion of lipid stores into waterproofing hydrocarbons at the onset of adulthood, allowing the animal to adapt to dry conditions and dietary sugars.