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

Abstract

Graphical Abstract Highlights d Lipid stores are consumed rapidly after Drosophila transitions into adulthood d Drosophila HNF4 directs fatty acid conversion to VLCFA and hydrophobic hydrocarbons d VLCFA/hydrocarbon synthesis ensures adaptation to dry conditions and dietary sugars d The role for HNF4 in regulating VLCFA synthesis is conserved between flies and mice SUMMARYAnimals 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, HNF4a 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.

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

“…Chronic activation of Toll signaling leads to a 80% decrease in adult viability, with most animals dying at the pharate adult stage (Roth et al, 2018). This decrease in viability is likely multifactorial, but impaired triglyceride levels likely lead to reduced metabolic energy to complete metamorphosis as well as a decrease in the pool of triglyceride that is needed to waterproof the adult cuticle (Storelli et al, 2019).…”

Drosophila PDGF/VEGF signaling from muscles to hepatocyte-like cells protects against obesity

“…Newly eclosed adult flies emerge from their pupal case with limited lipid stores in their adipose tissue. While the larval adipose tissue cells persists through metamorphosis, much of the lipids released from these cells are used up to form the water resistant barrier on their exoskeleton that protects them from dehydration (Storelli et al, 2019). The adipose tissue lipid stores are restored after emergence through feeding and de-novo lipid synthesis.…”

“…Similarly, in adult flies the oenocytes play a role in imparting starvation resistance by regulating production of very long chain fatty acids (VLCFAs) for waterproofing of the cuticle, especially when flies are starved under lower humidity conditions, and possibly by regulating lipid mobilization Storelli et al, 2019). We first investigated whether muscle-to-oenocyte Pvf1 signaling plays a role in starvation resistance.…”

“…When adult flies emerge from their pupal cases the adult adipose tissue has very low stored lipid content (Storelli et al, 2019), and adipose tissue cells of post-eclosion flies are also notably small in size ( Fig. S5).…”

Stored Lipids: More Than Mere Fuel

“…Stored lipids fuel early development, but with adulthood comes changing metabolic needs. In this issue of Developmental Cell, Storelli et al (2018) show that the Drosophila HNF4 nuclear receptor drives adults to convert lipids to very long chain fatty acids and hydrocarbons for an anti-dehydration function likely conserved in mice.…”