C. elegans develop tumor-like gonad abnormalities in early adulthood after extended L1 starvation followed by unlimited feeding. We determined that increased maternal oocyte provisioning of vitellogenin protects progeny from starvation-induced pathology by reducing insulin/IGF signaling (IIS) during larval development. Here we show L1 starvation and IIS interact to affect phosphatidylcholine (PC) metabolism and adult pathology. PQM-1/SALL2 activity is increased in fed worms following L1 starvation. Knock-down of the sole known IIS receptor
daf-2/InsR activates DAF-16/FoxO and inhibits PQM-1, and
pqm-1 RNAi during larval development reduces starvation-induced pathology. PQM-1 promotes fatty acid synthetase
fasn-1/FASN expression following L1 starvation, and mutation of
fasn-1 reduces starvation-induced pathology. Lipid profiling revealed L1 starvation increases PC abundance in early adulthood, and
daf-2 RNAi during development suppresses this increase in a
daf-16-dependent fashion. Powerful signaling molecules called oxylipins are derived from the oxidation of polyunsaturated fatty acid tails of PC. Oxylipins derived from arachidonic acid (AA), known as eicosanoids, are best studied.
fat-4/FADS2/FADS3 mutants, which cannot desaturate fatty acids to produce AA, are resistant to starvation-induced pathology. Mutation of the omega-3 fatty acid desaturase
fat-1 increases starvation-induced pathology, and
fat-4 is epistatic to
fat-1, suggesting elevated levels of AA or AA-containing phospholipids is oncogenic following early-life starvation. Indeed, lipid profiling revealed that PC species containing AA and other long polyunsaturated tails are particularly increased following L1 starvation. Furthermore, oxylipin profiling showed that
fat-4 mutants, which do not develop starvation-induced tumors, have reduced levels of eicosanoids. In addition, gene expression profiling suggests
fat-4 affects cell-cell adhesion and the innate immune system, suggesting consequences of eicosanoid signaling. Finally, treatment with an antioxidant during larval development suppressed starvation-induced pathology. Together, these findings provide insight into the metabolic consequences of early-life starvation, which can result in adult disease. Moreover, this study implicates IIS in regulation of PC metabolism, which plays an understudied role in regulation of critical factors governing growth and homeostasis including TOR, RAS, and PPAR.