mRNA-seq analysis of early adult C. elegans fatty acid synthesis mutant following extended L1 arrest

Early-life malnutrition increases adult disease risk in humans, but the causal changes in gene regulation, signaling, and metabolism are unclear. In the roundworm Caenorhabditis elegans, early-life starvation causes well-fed larvae to develop germline tumors and other gonad abnormalities as adults. Furthermore, reduced insulin/IGF signaling (IIS) during larval development suppresses these starvation-induced abnormalities. How early-life starvation and IIS affect adult pathology is unknown. We show that early-life starvation has pervasive effects on adult gene expression that are largely reversed by reduced IIS following recovery from starvation. Early-life starvation increases adult fatty-acid synthetase fasn-1 expression in daf-2 IIS receptor-dependent fashion, and fasn-1/FASN promotes starvation-induced abnormalities. Lipidomic analysis reveals increased levels of phosphatidylcholine in adults subjected to early-life starvation, and supplementation with unsaturated phosphatidylcholine during development suppresses starvation-induced abnormalities. Genetic analysis of fatty-acid desaturases reveals positive and negative effects of desaturation on development of starvation-induced abnormalities. In particular, the delta 3 fatty-acid desaturase fat-1 and the delta 5 fatty-acid desaturase fat-4 inhibit and promote development of abnormalities, respectively. fat-4 is epistatic to fat-1, suggesting that arachidonic acid, or lipids that contain it, promotes development of starvation-induced abnormalities. This work shows that early-life starvation and IIS converge on regulation of adult lipid metabolism, affecting stem-cell proliferation, tumor formation, and additional adult pathologies. Overall design: Two conditions (starved wild type (N2) and starved fasn-1(g14) mutants) with two biological replicates per condition.