Department of Biology, Duke University, Durham, United States; University Program in Genetics and Genomics, Duke University, Durham, United States
Dhaval P Bhatt
Duke Molecular Physiology Institute, Duke University, Durham, United States
Rojin Chitrakar
Department of Biology, Duke University, Durham, United States
Matthew D Hirschey
Duke Molecular Physiology Institute, Duke University, Durham, United States; Department of Medicine, Duke University, Durham, United States; Department of Pharmacology & Cancer Biology, Duke University, Durham, United States
daf-16/FoxO is required to survive starvation in Caenorhabditis elegans, but how daf-16IFoxO promotes starvation resistance is unclear. We show that daf-16/FoxO restructures carbohydrate metabolism by driving carbon flux through the glyoxylate shunt and gluconeogenesis and into synthesis of trehalose, a disaccharide of glucose. Trehalose is a well-known stress protectant, capable of preserving membrane organization and protein structure during abiotic stress. Metabolomic, genetic, and pharmacological analyses confirm increased trehalose synthesis and further show that trehalose not only supports survival as a stress protectant but also serves as a glycolytic input. Furthermore, we provide evidence that metabolic cycling between trehalose and glucose is necessary for this dual function of trehalose. This work demonstrates that daf-16/FoxO promotes starvation resistance by shifting carbon metabolism to drive trehalose synthesis, which in turn supports survival by providing an energy source and acting as a stress protectant.
